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Background The cytoarchitecturally defined Edinger–Westphal nucleus (EW) is now referred to by many investigators as the centrally-projecting EW (EWcp) in humans. Although the mature structure is well-characterized, there have been few reports describing the precise morphology of this nucleus during the second half of gestation. Subjects/Design Eleven brains were examined from preterm infants, aged 20–39 postmenstrual weeks, who died of various causes. After fixation, the brains were embedded in celloidin and serial sections of 30-μm thickness were cut in the horizontal plane. Sections were stained using the Kluver–Barrera method. In addition to microscopic observations, computerized 3D reconstruction and morphometry were performed. Results From 21 weeks, the EWcp had a distinctive, complex 3D structure comprising two or three parts. The dorsal part was arcuate, half encircling the oculomotor somatic nuclei (OSN). The rostral part was the most voluminous, ventral to the rostral OSN, extending anteriorly. The caudal part was the smallest, and was composed of several neuronal groups near the ventral tip of the OSN. In three cases, the caudal part was absent. It could also be joined to the rostral part, forming a ventral part. The total volume of the EWcp increased exponentially with age, and the ventral part grew more rapidly than the dorsal part. The mean neuronal profile area increased linearly with age, and the rate of increase was almost equal between the dorsal and ventral parts. Conclusions This study suggests that a distinctive, complex, two- or three-part 3D structure of the EWcp is preserved after mid-gestation, and that the ventral part of the EWcp may expand in volume more rapidly than the dorsal part.

Introduction This study described the prenatal development of the accessory olivary nuclei (AO) in humans. Materials/methods Serial brain sections from ten pre- and full term infants aged 21–43 postmenstrual weeks (PW) were stained using the Kluver–Barrera method. A computerized 3D-reconstruction technique and morphometry were adopted for the study. Results The medial AO (MAO) and dorsal AO (DAO) were identified at 21 PW. The dorsal cap was clearly differentiated from the main body (MB) of the MAO in neuronal cytoarchitecture. Pyknotic neurons were diffusely observed in the AO at 21 PW and were most concentrated in the MB. These neurons became infrequent from 28 PW onward. Neuronal nests existed in clusters between the AO and the medial lemniscus at 21 PW, which reduced progressively in size and number with age. The 3D-reconstructions showed that the AO are separated into caudal and rostral parts, and that this separation is achieved by mid-gestation in the DAO. Nuclear volume increased exponentially with age in the AO, although the rate of increase was half that of the principal nucleus (PO). Neuronal numerical density decreased rapidly 21–28 PW. The total neuronal number showed a weak correlation with age. The mean neuronal profile area increased linearly with age. Conclusion The human AO are separated into caudal and rostral parts in the fetal period. The nuclear volume and neuronal profile areas increase with age, although the rate of this increase is lower than in the PO. Natural neuronal death may occur at mid-gestation in the AO.

Introduction The lateral geniculate nucleus (LGN) is the major relay center of the visual pathway in humans. There are few quantitative data on the morphology of LGN in prenatal infants. In this study, using serial brain sections, the author investigated the morphology of this nucleus during the second half of fetal period. Material and methods Eleven human brains were obtained at routine autopsy from preterm infants aged 20–39 postmenstrual weeks. After fixation, the brain was embedded en bloc in celloidin and cut serially at 30 μm in the horizontal plane. The sections were stained at regular intervals using the Kluver–Barrera method. Results At 20–21 weeks, the long axis of LGN declined obliquely from the vertical to horizontal plane, while a deep groove was noted on the ventro-lateral surface of the superior half. At this time, an arcuate cell-sparse zone appeared in the dorso-medial region, indicating the beginning of lamination. From 25 weeks onwards, the magnocellular and parvocellular layers were distinguishable, and the characteristic six-layered structure was recognized. The magnocellular layer covered most of the dorsal surface, and parts of the medial, lateral, and inferior surfaces but not the ventral and superior surfaces. Nuclear volume increased exponentially with age during 20–39 weeks, while the mean neuronal profile area increased linearly during 25–39 weeks. Conclusion Human LGN develops a deep groove on the ventro-lateral surface at around mid-gestation, when the initial lamination is recognized in the prospective magnocellular layer. Thereafter, the nuclear volume increases with age in an exponential function.

Summary Background Precise anatomical data on the development of human oculomotor somatic nuclei (OSN) remain rare. Design/subjects This study describes the histology of human OSN in 11 preterm and full-term infants aged 20–43 postmenstrual weeks who died of various causes. Celloidin-embedded serial sections were stained with the Kluver–Barrera and other conventional methods including silver impregnation. To evaluate the growth of OSN quantitatively, the author estimated the nuclear volume and the average neuronal area on morphometry. Results Four subnuclei were identified at 20–21 weeks: the fascicular, principal, dorsal median, and ventral median nucleus. Early tigroid Nissl bodies appeared in presumed motoneurons by 27–28 weeks, then resembled adult Nissl bodies at birth. On silver impregnation, the oculomotor nerve roots, crossed or uncrossed fibers at the midline, and a plexus of efferent or afferent axons in the neuropil were observed at 20–21 weeks. Then, the plexus was elaborated to form a perineuronal net of thin axon terminals by 28–29 weeks. The nuclear volume of OSN exponentially increased with age over 20–43 weeks, while the average of neuronal profile areas linearly increased in each subnucleus; the coefficient of regression was largest in the principal nucleus, and the regression lines nearly overlapped among the other subnuclei. Statistical analysis confirmed that the average neuronal area was largest in the principal nucleus in older cases. Conclusion This study suggests that four subnuclei can be distinguished in human OSN by mid gestation, and that the principal nucleus may be different in neuronal cytoarchitecture from the others.

We describe a rare case of an acardiac twin (acardius anceps) with advanced brain development. Complete serial sections of the brain were made for microscopic observation and volumetric analysis. The cerebral surface showed unusual gyri and sulci with absence of the right olfactory bulb. Cortical lamination was almost normal, except for the insula where polymicrogyria and leptomeningeal neuroglial heterotopia were seen. The latter was also observed in the basal forebrain. Partial agenesis of the corpus callosum was noted with a very thick left cingulate gyrus. The anterior commissure did not cross the midline. Subcortical structures including basal ganglia, diencephalon, and brainstem/cerebellum appeared grossly normal, but hypo- or dysplasic changes were observed in some regions. The ventricles were enlarged and the left internal carotid artery was absent. In addition, porencephalic foci were located in the right temporal and parietal lobes. On comparative volumetry, the total brain was normal, but brain structures showed variable volumetric changes, with higher volume in the ventricles, diencephalon, and archi-/paleopallium, and lower volume in the periventricular germinal layer, basal ganglia, cerebral cortex, and brainstem/cerebellum. These observations showed that brain development can proceed nearly normally in acardia if blood flow is relatively preserved.

The concentrations of PCB congeners in the blubber and liver of mother Steller sea lions ( Eumetopias jubatus ; SSLs) and their fetuses from the coast of Hokkaido, Japan in 2008, 2010 and 2012 were analyzed by HRGC–HRMS, in order to elucidate PCB congener profiles and maternal-to-fetal transfer of PCBs in SSLs. ΣPCBs in the fetuses were 1400 ± 660 (the mean ± SD) ng/g-fat in the blubber and 570 ± 320 ng/g-fat in the liver, respectively. There was a concern that SSLs had been contaminated by PCBs during the fetal period. The concentrations of the major congeners in the blubber and liver were a correlation between the fetus and mother (blubber: r = 0.9934, liver: r = 0.9160; P ≦ 0.05). The results indicated that PCBs in the fetuses came from the mothers. #177 and #199 showed no correlations between the fetus and the mother in the blubber and liver. This indicated a selective capture by some natural protector such as the placenta.

The development of the human magnocellular red nucleus (RNm) was studied in 20 fetuses at 12-39 weeks of gestation (WG). With microscopic observation on serial sections of the brain, we measured the profile area of a neuronal cell body. At 12WG, several islands of immature cells of the RNm appeared dorsal to the parvocellular red nucleus (RNp). At 16WG, the RNm was detected ventral to the RNp as a cluster of semilunar shape, consisting of basophilic neurons of various sizes. During 18-23WG, the neurons were dispersed dorsal to the RNp. They were isolated or aggregated as small clusters among the myelinated oculomotor nerve roots. Twenty-eight WG onwards, the neurons were widely distributed ventrolateral to the superior cerebellar peduncle and around the caudal pole of the RNp. Measurement of the profile area revealed that the average size of overall neurons increased almost linearly with the gestational age, and that two populations (large and small neurons) were clearly distinguished on the histogram from 33WG onwards. The relative position of the RNm to the RNp may vary among the individuals, especially in earlier fetal stage. This study suggests that the differentiation and maturation of neuronal cytoarchitecture of the RNm may gradually and monotonously progress during the later half of gestation.

Brain abnormalities were described in a patient who had experienced Sjogren-Larsson syndrome (SLS) with typical clinical signs. Examination of the brain revealed (1) accumulation of peculiar lipoid substances stained lightly with periodic acid-Schiff (PAS) in the subpial, subependymal, and perivascular glial layers, the subpial and perivascular spaces, and the white matter of the cerebrum and brainstem; (2) proliferation of perivascular macrophages containing lipofuscin-like pigments; (3) dense distribution of round or ellipsoid small bodies stained strongly with PAS in the subpial, subependymal, and perivascular glial layers and the white matter; (4) appearance of spheroid bodies in the neuropil of relay nuclei (the lateral geniculate body, pontine nuclei, inferior olivary nucleus, posterior funicular nucleus, and dentate nucleus) and the white matter; and (5) reduction of myelinated nerve fibers in the cerebral and cerebellar white matter. Six-layered neuronal cytoarchitecture was preserved in the cerebral neocortex, except for the insula where pyramidal neurons were arranged at random. The exact mechanisms remain unclear, but it is suggested that peculiar lipoid substances may accumulate in the specific regions of the brain and that neuronal and astrocytic processes may be primarily affected in SLS.

We present an autopsy case of Larsen-like syndrome with unusually severe neurologic complications. The patient, a 3-year-old girl, manifested severe psychomotor retardation, tetraplegia, and intractable partial seizures as well as multiple joint dislocations with other skeletal deformities, minor external anomalies, and laryngotracheomalacia. Neuropathological examination of the brain revealed (1) cortical dysgenesis in the bilateral perisylvian region; (2) protrusions of the brain parenchyma into the subarachnoid space, (3) abnormal arrangement of olivary neurons, (4) dilation of the lateral ventricles with subventricular gliosis and multiple glial nodules, (5) hypoplasia of the cerebral white matter with subcortical astrocytosis, and (6) necrotic change in Sommer sector of the hippocampus. There were no microscopic abnormalities in the mesenchymal tissue of the brain (i.e., vascular walls and the meninges). Cortical dysgenesis in the perisylvian region was characterized by a zonal heterotopia of pyramidal and granule neurons in the molecular layer, which clinically may be closely related to intractable partial seizures in the orofacial area. Findings 1, 2, and 3 may represent a disturbance of neuroblast migration, speculated to have occurred during the latest stage of migration (around 20-25 weeks gestation). There are few published reports describing the combination of Larsen-like syndrome and brain dysplasia. Correlation of brain dysplasia with congenital skeletal abnormalities is unclear in our patient. We speculate that systemic hypoxic-ischemic insults during the second half of gestation and/or some genetic factors might be possible causes of brain dysplasia.

Background: The abducens nucleus directly innervates the lateral rectus muscle and plays a role in controlling conjugate horizontal eye movements. Although the neuronal cytoarchitecture of the abducens nucleus has been extensively investigated in various species of vertebrates, few studies have been undertaken in humans, especially in fetuses or neonates. Design/Subjects: We examined 12 human brains from preterm infants aged 20–43postmenstrual weeks to document the histology and morphometry of the abducens nucleus. The brain was processed into celloidin-embedded serial sections stained with the Kluver–Barrera and other conventional methods. Results: The nucleus was identified as a mass of cells as early as 20weeks. Its neurons were clearly distinguished from glial cells due to droplet-like, clear nuclei containing prominent nucleoli and surrounded by a basophilic perikaryon. Neurons of various sizes and shapes were intermingled within the nucleus, although larger neurons were located towards the center of the nucleus. Immature granular or reticular Nissl bodies were seen at 20–21weeks. Tigroid, coarse Nissl bodies appeared around 28–29weeks in larger neurons, although in smaller neurons Nissl bodies were dispersed or concentrated peripherally. Morphometric results were: (1) the nuclear volume exponentially increased with age between 20 and 43weeks; (2) the histograms of neuronal profile areas showed a non-normal distribution trailing toward the right and widening with age; (3) the geometric average of neuronal profile areas increased linearly with age. Conclusion: Our study suggests that the human abducens nucleus enlarges more quickly toward the end of gestation, and comprises heterogeneous groups of neurons.

Summary Background The trochlear nucleus, the smallest of the extraoculomotor nuclei, is unique or even curious, because the nerve roots emerge dorsally from the superior medullary velum after decussation. Little information is available on the developmental anatomy of this nucleus in humans. Design/subjects We examined serial brain sections from 10 premature infants aged 20–39 weeks of gestation to document the histology and morphometry. Results The trochlear nucleus was composed of three parts: the rostral tip, the main body, and the caudal division. The rostral tip was a rostral continuation of the main body, being closely related to the oculomotor nucleus; the main body was enveloped by a fibrous capsule; the caudal division was a small separate cluster of neurons in the medial longitudinal fasciculus or the root fibers with individual variations. Tigroid Nissl bodies first appeared at 28 weeks in presumed motoneurons. Various sizes of motoneurons were recognized; medium-sized to small motoneurons were preferentially accumulated in the rostral tip. Among the motoneurons, presumed non-motor neurons were infrequently scattered. Morphometric analysis showed that the nuclear volume exponentially increased with age, about 15 fold over 20–39 weeks, while the average profile area of the neurons linearly increased. Statistical analysis confirmed that cell area was smallest in the rostral tip among the three parts. Conclusion Although the sample number is small in this study, it suggests that the human trochlear nucleus can be divided into three parts, and that the overall growth may be accelerated at about 30 weeks of gestation.

We previously reported the effects of cyclic therapy with etidronate (CTE) on periprosthetic bone mineral density (BMD) after cementless total hip arthroplasty (THA). This study aimed to evaluate the effects of withdrawal and intervention of CTE after cementless THA. The control group consisted of 24 patients without osteoactive drugs. Sixteen patients continued on CTE (i.e., 400 mg/day oral etidronate for 2 weeks followed by 12 weeks of 500 mg/day calcium lactate, repeated every 14 weeks) for the first 12 months followed by no treatment for 18 months (early-etidronate group). Fifteen patients received no treatment for the first 18 months followed by CTE for 12 months (late-etidronate group). Periprosthetic BMD in seven regions of interest based on the zones of Gruen et al. was measured with dual energy X-ray absorptiometry at 3 weeks, 6, 12, 18, 24, and 30 months postoperatively. At 12 months after operation (off therapy point in the early-etidronate group), postoperative decreases of BMD in the early-etidronate group were significantly smaller than those in the control group in zones 1, 2, 5, 6, and 7 and those in the late-etidronate group in zones 1, 5, 6, and 7 (P < 0.05 for each). In the early-etidronate group, significant decreases in BMD were found during months 12–30 (off therapy period) after withdrawal of CTE in zones 1 and 7 (P < 0.05 for each). In the late-etidronate group, BMD increased significantly in zones 4 and 6 (P < 0.05 for each) during months 18–30 (on therapy period) after intervention trial, while in the controls, BMD decreased significantly in zone 3 (P < 0.05) over this period. At the final follow-up (30 months), BMD loss in zone 7 was significantly less in the early-etidronate group than in the other groups (P < 0.05). BMD changes in the early-etidronate group and late-etidronate group were associated with changes in biochemical bone markers.

The neuropathological findings in an autopsy case of thanatophoric dysplasia (TD) with serial sections of the brain are described here. This patient was a female infant, born at 33 weeks gestation, who died on day 1. Skeletal anomalies, consisting of short limbs, a small thorax, short ribs, thick cortical vertebral body substance and sternum substance, and hypoplastic lungs, were compatible with typical phenotypic features of TD. The brain weighed 370 g, showing a cloverleaf megalencephaly. A computerized 3-D reconstruction technique visualized clearly abnormal deep sulci arranged perpendicular to the neuraxis on the inferior surface of the temporal lobe, and peculiar configurational changes of the lateral ventricle. In particular, the inferior horn showed an unusual complex form. Dysgenetic changes were largely located in the anterior temporal lobe as follows: cortical polymicrogyria; leptomeningeal heterotopia with discontinuity of the subpial basement membrane; serpentine arrangement of pyramidal cells of the cornu ammonis (CA)1 of the hippocampus; hypoplastic dentate gyrus; hyperplasia of the amygdaloid body; and heterotopic nodules of neuroblasts or glioblasts in the periventricular white matter. Apart from the temporal lobe, the cerebral pia mater showed unusual fusion of two facing sheets in a sulcus and ectopia of nerve cells, and the cerebellar vermis was small. The findings observed here indicate that overgrowth and lack of growth can coexist in the TD brain, suggesting that some interaction(s) between the mesenchyme and the nervous tissue may play a role in normal differentiation of these two cell lines.

The morphometric development of the human cerebellar nuclei was examined in 9 fetuses (16–40 weeks of gestation; WG) an infant (2 months old) and 2 adults (16 and 63 years old). With the morphological observation of serial sections of the brain containing the cerebellar nuclei, the authors measured sections to get several morphometric parameters: the volume of nuclear column and number, packing density and cell body area of neurons. Each nucleus (dentate emboliform, globose and fastigial nucleus) was recognized even at 16 WG. Nerve cells containing Nissl bodies were observed in all nuclei after 23 WG. Degenerative changes were detected in some neurons for every nucleus at 21 and 23 WG. Three stages were observed in the developmental course of nuclear volume and neuronal packing density: the primary or undifferentiated stage at 16 WG, the secondary stage with variability at 21–32 WG and the tertiary stage with monotonous increase (nuclear volume) or gradual decrease (neuronal packing density) after 35 WG. No significant correlation between neuronal number and gestational age was noticed for every nucleus. The analysis of cell body area (neuronal size) demonstrated that the dentate neurons developed after the intermediate or fastigial neurons. It is concluded that there is a critical period between slightly before 20 WG and slightly after 30 WG, matched with the secondary stage in the development of the cerebellar nuclei.