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The aim of this radiographic study of human fetuses was to examine the pattern and sequence of ossification in the occipital bone and the spinal vertebrae. Together with previous studies of ossification of the human fetal basal cranium, this study can serve as a reference for normalcy in future studies of fetuses with neural tube defects and associated pathological development of the axial skeleton. Thirty-nine normal fetuses aborted between 9 and 14 weeks of gestation were examined. Based on the appearance of ossification centers in the bones under study, the fetuses could be grouped in four well-defined developmental stages, which were named occipito-spinal stages I-IV (OS I-IV). The OS stage was closely related to gestational age, crown-rump length, foot length, and degree of ossification in the hands and feet.

The incisive fissure and the transverse palatine suture are well known anatomical structures in the human palate. The purpose of the present study was to describe the development and the morphology of the incisive fissure and the transverse palatine suture. Another purpose was to compare the nature of both structures with the aim of elucidating their possible function in the developing facial skeleton. Descriptions of the initial formation, development, and maturation of the incisive fissure and the transverse palatine suture, in combination with a comparison between the suture systems, were not found in the literature. Human fetal material, consisting of a total number of 96 specimens with gestational ages ranging from 9 to 24 weeks, was analyzed macroscopically (radiologically and after devisceration) and microscopically (histologically). The bony maturation of specimens was recorded by relating to the stages of maxillary ossification (MAX), an index for skeletal maturity of the palate. The study revealed pronounced macroscopic and microscopic differences between the incisive fissure and the transverse palatine suture. The transverse palatine suture appears to be a site for anteroposterior growth of the palate. The incisive fissure has a different macroscopic and microscopic appearance and presumably has a function more closely related to the development of the dentition and the anterior part of the maxilla.

Closure of the palatal shelves during normal prenatal palate formation is commonly supposed to be the result of a complex interaction between tissue growth processes and functional factors such as mandibular and tongue movements. The purpose of the present study was to analyze tongue and palatine bone positions during palatal shelf closure. The material consisted of 40 normal human fetuses (CRL 26-57 mm). The series covers the developmental stages in which palatal shelf closure takes place. The spatial relation between the tip of the tongue and the lips was examined by visual inspection, and radiographic/cephalometric methods were used for analyzing palatine bone positions. On axial radiographs of the upper jaws, the angle in the horizontal plane between the vertical plates of the palatine bones was measured. The study revealed that the vertical plates of the palatine bones rotate on their vertical axes during palatal closure, the mean interpalatine angle changing from 23.7 degrees (SD 2.0 degrees) to 13.3 degrees (SD 3.2 degrees), P < 0.001. The rotation of the palatine bones occurred while the cranial base was still unossified. Moreover, the tip of the tongue became visible between the lips immediately after palate closure. In the present study the rotational changes observed in skeletal tissue provided information about soft tissue changes during palatal closure. These normal developmental aspects are discussed in relation to skeletal deviations in congenital cleft palate malformations.

Much attention has been focused on the mechanisms responsible for the elevation and fusion of the palatal processes during formation of the secondary palate. In a former publication this closure, defined as fusion of the palatal shelves along their length, was described as occurring at a period in osseous palatal development characterized by incipient ossification of the maxillae and palatine bones, and at a stage in early mandibular development when the mandibular condyle has not developed. The purpose of the present study was to examine the osseous maturation of the cranial base at the time of palatal closure. The investigation was based on 62 human embryos and fetuses, CRL 22-57 mm, and general skeletal hand and foot maturation CNO = 0-0 to CNO = 8-1 (CNO, Composite Number of Ossified bones in hand and foot). From the fetuses, cranial tissue was dissected out and skeletal maturity was determined radiographically according to formerly described skeletal maturity stages in the cranial base. The study revealed that the soft tissue palatal shelves always elevate and fuse along their length at a specific, well-defined stage of maturity in the cranial base. The cranial base development in this stage is characterized by unossified cartilage. This information is essential for understanding abnormal skeletal development of the oral and nasal cavities.

The purpose of the present study was to describe normal midsagittal craniofacial morphology in second trimester human fetuses. Measurements of the cranial base angle and the prognathism of the maxilla and the mandible were performed on radiographs of cranial midsagittal tissue blocks of 52 fetuses with a gestational age from 13 to 27 weeks. Special procedures were developed for the definitions of the nasion and sella reference points on the radiographs in the early stages of fetal development. Mean data were reported for stages of crown rump length (CRL) and maturation of the fetal cranial base (MSS), usable as reference in assessment of pathological fetal crania in reports and autopsy procedures. Regression equations were determined for the regression of the angular values on CRL, MSS, and general skeletal maturation (TNO). The cranial base angle was found to decrease significantly, and the angles of prognathism to increase significantly with increasing CRL, TNO, and MSS values. It was suggested that these simultaneous and similar changes in the three angles could be accounted for by the upwards movement of the sella point produced by a cranial displacement of the pituitary fossa caused by local cartilagenous growth and bony remodelling during the period of study. The study thus reflects the influence of cranial skeletal maturation on the early development in shape of the craniofacial complex.

Craniofacial skeletal development in eight human holoprosencephalic fetuses from second trimester abortions were examined by radiography and histology. The whole spectrum of associated facial malformations from anophthalmia through cyclopia, ethmocephaly, cebocephaly, and median cleft lip to short philtrum was represented. Cases with the most severe facial malformations also had the most severely affected facial skeleton. In the facial skeleton, the premaxilla was most often affected; it was absent in seven cases and malformed in the one with only a short philtrum. This and other facial skeletal malformations can be explained as abnormal fusion of the facial bones because of defective development of the nasal cartilage. The occipital bones were normal, but the basicranial skeleton anterior to the spheno-occipital junction was affected in all cases. The findings support the hypothesis that the facial malformations in holoprosencephaly result from disturbance in embryonal life of the mesoderm at the rostral end of the notochord.

A Danish anthropological collection of medieval human skeletons excavated in 1986 involves a mandible (No. 212) from an adult female born without the lower alveolar nerve and mandibular canal. It is believed that the defect has resulted in lack of tooth development on the affected side and that the mylohyoid nerve has partially compensated for this defect by development of teeth in localized areas. The defective mandibular dentition has caused a compensatory development of the alveolar process in the maxilla. The missing occlusal support has altered muscular traction on the mandible. This has caused an alteration in mandibular shape. Whether the asymmetric development of the mandible is caused by muscular dysfunction, by failure in angular growth apposition, or by a combination of these factors is discussed. The case presents valuable data in the ongoing discussion about the interaction between nerve tissue and tooth formation and about the interaction between occlusion, jaw morphology, and muscular traction. The study shows how archeological material in an interdisciplinary cooperation between archeological, embryological and orthodontic research can contribute to the clarification of current biological problems.

The factors initiating the onset of desmal jaw formation are not known. The purpose of the present report was to examine the correlation between the appearance of ossification and nerve tissue in human fetal jaws. This was done through elaboration of similarities in occurrence of tissue types at four different sites of initial bone formation in the jaws. Radiological and histochemical methods applied to the jaws of 26 human embryos/fetuses revealed that nerve tissue appeared in the jaws before bone tissue. Early bone formation occurred in close relation to the mandibular nerve, the maxillary nerve, the palatine nerve, and the naso-palatine nerve. It is suggested that the foramina (mental foramen, infraorbital foramen, palatal foramen, and incisive foramen) are the areas of incipient bone formation, and that the sequence in bone formation corresponds to the sequence in the development of nerve fibers from the trigeminal ganglion.

In a previous investigation on prenatal development of the human cranial base, the sequence in which the bones develop in the midsagittal region was elucidated. The purpose of the present study was to identify fetal ossification on horizontal plane roentgenograms of the occipital and sphenoid bones in the central part of the cranial base, and establish stages in bone appearance related to general fetal developmental parameters. This study is based upon roentgenograms of the cranial base of 145 human fetuses from the first half of the prenatal period. Two different maturation patterns of the sphenoid bone were observed. The first, most common pattern is characterized by a midsagittal centre of ossification and the second by bilateral centres of ossification in the corpus of the sphenoid bone. These bilateral centres might in some cases be connected by a slight bony bridge. It appears that these different maturation patterns are maintained throughout the period investigated. The material was divided into five well-defined developmental stages for both maturation patterns and general parameters of fetal development. Mapping different aspects of ossification in normal cranial development is necessary for understanding deviations of cranial maturation and growth.

The purpose of the present investigation has been to analyse prenatal cranial base development in the coronal plane and to combine the findings with results in former reports on cranial base maturation estimated in the horizontal and sagittal planes. The study is based upon cranial bases of 26 human fetuses from the first half of the prenatal period. Fetal coronal plane cranial base tissue blocks were dissected, radiographed, and sectioned for microscopic examination. Five stages in cranial base development are defined and related to general parameters for fetal size and fetal maturation. Two different maturation patterns were recognized in the sphenoid corpus. Canal structures, remnants of the craniopharyngeal canal, were observed in specimens showing bilateral centers of ossification in the sphenoid corpus. The radiographic method used is easy to record and recommended for diagnosing prenatal and neonatal cranial malformations.

A new radiography technique for examining second trimester abortions permits an accurate analysis of growth and maturation of the fetal skull. Reference material for normal development has been previously published. The potential of the method is demonstrated with three examples: thanatophoric dysplasia, Arnold-Chiari malformation, and anencephaly.

Previous investigations of prenatal development of the human cranium have not identified the sequence of its ossification. The purpose of the present study was to elucidate the pattern of skeletal maturity of the cranial bones in the midsagittal region anterior to the foramen magnum. This study is based upon a radiographic and histochemical investigation of midsagittal tissue blocks of the cranial bases of 73 human fetuses derived from the first half of the prenatal period. A marked regularity in the ossification pattern of the bones in the midsagittal part of the human cranium was observed. Ossification starts in the frontal bone. The sequence in which the next bones ossify is occipital bone, basisphenoid bone, presphenoid bone, and ethmoid bone. The material was divided into 7 maturity stages devised for this analysis. The stages were related to general fetal size (crown-rump length) and to general fetal maturation (composite number of ossified bones in hand and foot). Skeletal development of the median part of the human cranium is not strictly correlated with the size or the stage of general maturation of the fetuses. Knowledge of normal skeletal development is necessary for understanding anomalies of development.

The formation and early prenatal location of the human mental foramen was investigated on 43 human fetuses. Histochemical methods supplemented by macroscopic visualization were used. Similar studies on the mental foramen were not available in the literature. The study demonstrated constancy in the developmental sequence of the bony structures in the region of the mental foramen. The formation of the mental foramen was described and related to general developmental parameters such as CRL and CNO values (skeletal maturity indexes of the hand and foot). The study indicated that the very early position of the mental foramen was in the region of the interstitial bone between the primary canine and the primary first molar. A positional change in the dorsal direction was described during the first half of the prenatal period.

On the basis of morphological and histochemical studies of 71 human mandibles from the former half of prenatal life, five stages (D I to D V) in the development of the deciduous mandibular incisors are described. These stages are related partly to general parameters of fetal development, such as M age (menstrual age), CRL (crown-rump length), CNO (composite number of ossified bones in hand and foot) and partly to stages in the skeletal development of the symphysis menti (SM I to SM V). The investigation revealed close relationship between the development of the deciduous mandibular incisors and the skeletal development of the deciduous mandibular incisors and the skeletal development of the mandible in the region of the incisors. No such relationship was found between the development of the deciduous mandibular incisors and general parameters of fetal development.

In 51 human fetuses from the first half of the prenatal period, developmental stages in the symphysis menti and the mandibular condyle were assessed by histochemical reactions. The study showed the association between the timing of the developmental stages in the two mandibular growth zones.

Histochemical investigations on the symphysis menti region were performed on 72 human embryos and fetuses of crown-rump lengths (CRL) ranging from 16 to 162 mm, presenting skeletal maturity indices (CNO = composite number of ossified bones in the hand and foot) ranging from 0-0 to 19-11. The symphysis menti region is described in five developmental stages according to morphology and histochemical reactions at the interzone, enchondral bone formation, and Meckel's cartilage. The stages are described according to histochemical reactions for glycosaminoglucuronoglycans, collagen, glycogen, alkaline and acid phosphatase, and non-specific AS esterase. Silver impregnation followed by X-ray and histochemical control for Ca++ deposits supplemented the study. Special attention was paid to a fusion of the bilateral Meckel's cartilages in the midline characteristic of stage II. This is a finding not previously recorded in human fetuses. It is suggested to designate this fusion 'the rostral connection'. Histochemically, the fusion appeared as ordinary cartilage matrix (chondroitin-4- and/or-6-sulphate). The absence of a rostral connection characteristic of stage III is discussed. On the basis of reactions for glycosaminoglycans and activity of hydrolytic enzymes, the symphysis is characterized as a growth zone, active in mandibular growth in width as well as in length, during the first half of the prenatal period. The material available did not justify a description of skeletal development in the symphysis menti as a function of CRL, of skeletal maturation in the hand and foot, or as a function of a combination of these parameters.

Histochemical investigations on the mandibular condyle were performed on 72 human embryos and fetuses of crown-rump lengths (CRL) ranging from 26 to 186 mm, representing skeletal maturity indices expressed in CNO values (CNO = composite number of ossified bones in the hand and foot) ranging from 0-0 to 19-12. The development of the mandibular condyle is described according to morphology and to histochemical reactions for glycosaminoglucuronglycans, collagen, glycogen, alkaline and acid phosphatase, and nonspecific AS esterase. The development is described for (1) the bony component of the mandibular condyle, (2) the condylar cartilage, and (3) the fibrous cover of the mandibular condyle. For each tissue component, maturation steps are set up and included in the total evaluation of the condylar maturity stages. The developmental sequence set up on the basis of the morphologic and histochemical findings was followed by all condyles investigated. From this it may be presumed that the developmental sequence in human mandibular condylar components is constant during the former half of the prenatal period. The material available did not justify a description of skeletal development in the mandibular condyle as a function of fetal size, CRL, or skeletal maturity in the hand and foot.

Synthetic 1alpha-hydroxycholecalciferol, a potent vitamin D analogue, was given daily together with calcium to seven patients with senile osteoporosis and to three patients with prednisone-induced bone loss. Quantitative bone histology indicated increased formation and mineralization after three months of treatment. The bone resorption was reduced, a finding supported by a decrease in the urinary hydroxyproline excretion. Photon absorptiometry of the forearm showed a significant rise in the bone mineral content, in accordance with the histological findings. Serum calcium rose in all patients and severe hypercalcemia developed in one case. Urinary excretion of calcium and magnesium increased significantly. The findings indicate that treatment with 1alpha-hydroxycholecalciferol may be useful in osteoporosis due to aging or following corticosteroid administration. The patients must be carefully followed up because of the risk of hypercalcemia.

Seven patients with osteoporosis of ageing were treated with synthetic 1alpha-hydroxycholecalciferol (1alpha-H.C.C.) for 3-4 months. The compound was given at a daily oral dose of 2 mug together with an oral supplement of 1 g of calcium. Clinically there was a striking improvement in the patients' physical fitness. Increased bone formation and mineralisation were seen on iliac-crest bone biopsy, and this was supported by an increased osteoblastic activity demonstrated by histochemical measurement of alkaline-phosphatase activity. Bone histology furthermore showed a reduced bone resorption, which was supported by a reduced urinary excretion of total hydroxyproline. Photon absorptiometry of the forearm accorded with the histological findings, showing a significant increase in the bone mineral content. Serum-calcium rose in all patients, one developing a severe transitory hypercalcaemia. The urinary excretion of calcium and magnesium increased significantly. The serum concentrations of 25-hydroxycholecalciferol and parathyroid hormone were not significantly affected by the treatment. It is concluded that 1alpha-H.C.C. is an effective tool in the treatment of senile osteoporosis.

Previous investigations on the prenatal development of the human maxilla have focused mainly on the elevation and fusion of the soft tissue palatal shelves. The bony development has received only sporadic attention. The aim of the present investigation was to analyze and set up bony developmental stages in the human maxilla, as knowledge of normal skeletal developmental course, which has never been elucidated, is the prerequisite to understanding the abnormal course of development. The present study was based on a radiographic and histochemical investigation of maxillae from 104 human embryos and fetuses from the first half of the prenatal period. A marked regularity in the maxillary ossification pattern was observed, and consequently seven maturity stages, Max I-Max VII, were described. The material was divided according to these stages and related to general fetal size (crown-rump length) and to general fetal maturation (composite number of ossified bones in hand and foot). The material available did not justify a description of skeletal development of the maxilla as a function of CRL or CNO.

The purpose of the present study was to elucidate the stages of skeletal maturation of the maxilla and the mandible at the time of soft tissue palatal closure. Similar studies were not found in the literature. This investigation was based on maxillae and mandibles from 19 human embryos/fetuses selected by visual inspection of palatal structures, eight fetuses "just before palatal closure," and 11 fetuses "just after palatal closure." The findings are related to formerly described skeletal developmental stages in the maxilla, to stages in the symphysis menti region, and to development in the mandibular condylar region. The present study revealed that elevation of the palatal shelves takes place at a specific stage of maxillary skeletal maturity (stage Max III), at a time of mandibular development characterized by absence of condylar cartilage and by constancy in symphysis menti maturity (stage SM I). Knowledge of the normal sequence of prenatal skeletal development is considered essential for understanding the abnormal sequence of skeletal development.

Electron-dense granules in mitochondria from prenatal human osteoblasts, postnatal human osteoblasts, and from osteoblasts derived from a child with osteogenesis imperfecta congenita are described. The mitochondrial granules were of about 600 A in diameter and were attached to the mitochondrial cristae. Sections of mitochondria from prenatal osteoblasts showed an average number of 10 granuales per mitochondrial section, whereas sections of mitochondria of postnatal osteoblasts showed only occasionally 1-2 granules per mitochondrial section. Mitochondria from osteoblasts derived from the child with an untreated osteogenesis imperfecta congenita showed an average number of 10 granules per mitochondrial section.