Morphology and morphometry of the human embryonic brain: A three-dimensional analysis.

The three-dimensional dynamics and morphology of the human embryonic brain have not been previously analyzed using modern imaging techniques. The morphogenesis of the cerebral vesicles and ventricles was analyzed using images derived from human embryo specimens from the Kyoto Collection, which were acquired with a magnetic resonance microscope equipped with a 2.35-T superconducting magnet. A total of 101 embryos between Carnegie stages (CS) 13 and 23, without apparent morphological damage or torsion in the brain ventricles and axes, were studied. To estimate the uneven development of the cerebral vesicles, the volumes of the whole embryo and brain, prosencephalon, mesencephalon, and rhombencephalon with their respective ventricles were measured using image analyzing Amira™ software. The brain volume, excluding the ventricles (brain tissue), was 1.15 ± 0.43 mm(3) (mean ± SD) at CS13 and increased exponentially to 189.10 ± 36.91 mm(3) at CS23, a 164.4-fold increase, which is consistent with the observed morphological changes. The mean volume of the prosencephalon was 0.26 ± 0.15 mm(3) at CS13. The volume increased exponentially until CS23, when it reached 110.99 ± 27.58 mm(3). The mean volumes of the mesencephalon and rhombencephalon were 0.20 ± 0.07 mm(3) and 0.69 ± 0.23 mm(3) at CS13, respectively; the volumes reached 21.86 ± 3.30 mm(3) and 56.45 ± 7.64 mm(3) at CS23, respectively. The ratio of the cerebellum to the rhombencephalon was approximately 7.2% at CS20, and increased to 12.8% at CS23. The ratio of the volume of the cerebral vesicles to that of the whole embryo remained nearly constant between CS15 and CS23 (11.6-15.5%). The non-uniform thickness of the brain tissue during development, which may indicate the differentiation of the brain, was visualized with surface color mapping by thickness. At CS23, the basal regions of the prosencephalon and rhombencephalon were thicker than the corresponding dorsal regions. The brain was further studied by the serial digital subtraction of layers of tissue from both the external and internal surfaces to visualize the core region (COR) of the thickening brain tissue. The COR, associated with the development of nuclei, became apparent after CS16; this was particularly visible in the prosencephalon. The anatomical positions of the COR were mostly consistent with the formation of the basal ganglia, thalamus, and pyramidal tract. This was confirmed through comparisons with serial histological sections of the human embryonic brain. The approach used in this study may be suitable as a convenient alternative method for estimating the development and differentiation of the neural ganglia and tracts. These findings contribute to a better understanding of brain and cerebral ventricle development.

Encephalitis caused by human herpesvirus-6B in pancreas-after-kidney transplantation.

Human herpesvirus-6 (HHV-6) is a common pathogen among children, classically presenting with fever and rash that resolves without specific therapy. HHV-6 can be reactivated in the immunosuppressed patient. After bone marrow and solid organ transplantation, HHV-6 has been linked to various clinical syndromes, including undifferentiated febrile illness, encephalitis, myelitis, hepatitis, pneumonitis, and bone marrow suppression. However, HHV-6 encephalitis after pancreatic transplant has rarely been reported. Early diagnosis and treatment of HHV-6 encephalitis may be important for affected patients. We report the case of a 53-year-old pancreas-after-kidney transplant recipient who initially presented with high fever and confusion 3 weeks after operation. We managed to save the patient's life and preserve the pancreas graft function. We also review previously reported cases of HHV-6B encephalitis in solid organ transplant recipients.

Comparative analyses of paediatric dental measurements using plaster and three-dimensional digital models.

AIM: Recent advances in three-dimensional imaging have led to an increased interest in the application of computer-models in paediatric dentistry. However, in evidence-based paediatric dentistry the accuracy of new methods must be validated before they are introduced to clinical practice. We aimed to compare the accuracy of measurements of digital models obtained using a non-contact 3D measuring system, with direct measurements made on plaster models (gold standard) from children. MATERIALS AND METHODS: Twelve pairs of plaster models were obtained from children with deciduous dentition; tooth size, arch width, and arch length were examined. The same parts on each cast were measured twice with at least a 2-week interval between measurements with each method by four examiners. Linear mixed-effects model analyses were performed for comparison of values from the 2 different measurement methods. RESULTS: The average difference between the 2 methods in measured values, derived from the final model, was <0.2 mm. Random effect of examiners was always the smallest component of variance, and frequently negligible. STATISTICS: Intraclass correlation coefficients were typically >90%. CONCLUSION: These results suggest that primary dentition analysis of digital models has a high accuracy level, comparable to that of direct measurement of plaster models by digital calipers.

Application of three-dimensional digital models for the morphometric analysis of predentition plasters: accuracy and precision.

AIM: This study aimed to test the accuracy and precision of measurements of three-dimensional (3D) digital models from the pre-dentition period using a noncontact 3D measurement system (3D scanner) versus the gold standard method of direct measurements using a digital caliper on plaster models. MATERIALS AND METHODS: Ten pairs of plaster models were obtained from children during the predentition period. Linear measurements were performed using both methods. Three operators were trained in the use of both methods for this study. Measurements were performed with a minimum 2-week interval between measurements in a randomly chosen order. RESULTS: The mean difference between the measured values using the two methods was <0.2 mm for each measurement. There was no linearity in the measurements using pre-dentition digital models. An ANOVA Gage R&R analysis revealed that there was no significant operator difference (P < 0.307). The rate of variation of the 3D scanner over the total variation was 2.8%. The ICC was 0.982 (P< 0.001), suggesting excellent interoperator agreement. CONCLUSION: The results suggest that measurements of digital 3D pre-dentition models are highly accurate and precise, and also comparable to measurements using the gold standard method.

Strongly spin-orbit coupled two-dimensional electron gas emerging near the surface of polar semiconductors.

We investigate the two-dimensional highly spin-polarized electron accumulation layers commonly appearing near the surface of n-type polar semiconductors BiTeX (X=I, Br, and Cl) by angular-resolved photoemission spectroscopy. Because of the polarity and the strong spin-orbit interaction built in the bulk atomic configurations, the quantized conduction-band subbands show giant Rashba-type spin splitting. The characteristic 2D confinement effect is clearly observed also in the valence bands down to the binding energy of 4 eV. The X-dependent Rashba spin-orbit coupling is directly estimated from the observed spin-split subbands, which roughly scales with the inverse of the band-gap size in BiTeX.

Tumour suppressive microRNA-874 regulates novel cancer networks in maxillary sinus squamous cell carcinoma.

BACKGROUND: On the basis of the microRNA (miRNA) expression signature of maxillary sinus squamous cell carcinoma (MSSCC), we found that miR-874 was significantly reduced in cancer cells. We focused on the functional significance of miR-874 in cancer cells and identification of miR-874-regulated novel cancer networks in MSSCC. METHODS: We used PCR-based methods to investigate the downregulated miRNAs in clinical specimens of MSSCC. Our signature analyses identified 23 miRNAs that were significantly reduced in cancer cells, such as miR-874, miR-133a, miR-375, miR-204, and miR-1. We focused on miR-874 as the most downregulated novel miRNA in our analysis. RESULTS: We found potential tumour suppressive functions such as inhibition of cancer cell proliferation and invasion. A molecular target search of miR-874 revealed that PPP1CA was directly regulated by miR-874. Overexpression of PPP1CA was observed in MSSCC clinical specimens. Silencing of the PPP1CA gene significantly inhibited cancer cell proliferation and invasion. CONCLUSION: The downregulation of miR-874 was a frequent event in MSSCC, which suggests that miR-874 functions as a tumour suppressive miRNA, directly regulating PPP1CA that has a potential role of an oncogene. The identification of novel miR-874-regulated cancer pathways could provide new insights into potential molecular mechanisms of MSSCC oncogenesis.

[Delayed traumatic diaphragmatic hernia with strangulated stomach; report of a case].

A 30-year-old male who had suffered from the left hemopneumothorax due to the traffic accident 13 years before was admitted to our hospital suffering from abdominal pain. Computed tomography revealed the stomach was incarcerated through the left central tendon of the left diaphragm. He was diagnosed as delayed traumatic diaphragmatic hernia and emergency operation was performed via thoracic approach. Stomach and omentum, densely adhered to the lung and the chest wall, were strangulated in the left pleural cavity and hardly reducible. Stomach and omentum were reduced through the enlarged hernia and necrotized stomach was totally resected under the subsequent laparotomy. Hernia was closed directly via thoracic approach. A prompt diagnosis is necessary for a case highly suspicious of delayed traumatic diaphragmatic hernias presenting with strangulation.

Proteome analysis of human placentae: pre-eclampsia versus normal pregnancy.

Although placental proteins play multiple roles in fetal and placental development and in the maintenance of pregnancy, many remain inadequately characterized. In the present study, we comprehensively analyzed these proteins by using a proteomic approach. Samples were denatured with guanidine hydrochloride, which was found to be superior to the commonly used urea for the present purpose, and subjected to 2-dimensional (2D) electrophoresis (2-DE) to obtain placental proteome maps. The identified protein spots (ca. 60% of the total) on the proteome maps included several pregnancy-related proteins (PRPs). Furthermore, a novel 2D immunoblotting (2-DI) analysis of molecules related to pre-eclampsia revealed three immunopositive spots that appeared to correspond to dynactin p-50, a protein related to cell turn-over. The rate of positivity for dynactin p-50-reactive antibodies was significantly (P=0.0024) higher in 26 pre-eclamptic women than in 58 normally pregnant women. These results indicate that dynactin p-50 may be involved in the pathophysiology of pre-eclampsia.

Occlusal force and condylar motion in patients with anterior open bite.

Patients with open bite often show a weak occlusal force and temporomandibular disorders (TMDs). If these are the main cause of open bite, it may be hypothesized that both pre-pubertal and adult open-bite patients would show a weak occlusal force and abnormal condylar motion. The purpose of this study was to test this hypothesis. Test group subjects consisted of 13 consecutive pre-pubertal and 13 adult patients with anterior open bite. They were compared with age-matched normal subjects. The adult open-bite group showed a weaker occlusal force and a shorter range of condylar motion compared with the control subjects. In the pre-pubertal subjects, however, there were no significant differences in the occlusal force and range of condylar motion between the open-bite and control groups. Therefore, these results suggest that a weak occlusal force or TMDs may not be the main cause of open bite.

Three-dimensional morphology of the human embryonic brain.

The morphogenesis of the cerebral vesicles and ventricles was visualized in 3D movies using images derived from human embryo specimens between Carnegie stage 13 and 23 from the Kyoto Collection. These images were acquired with a magnetic resonance microscope equipped with a 2.35-T superconducting magnet. Three-dimensional images using the same scale demonstrated brain development and growth effectively. The non-uniform thickness of the brain tissue, which may indicate brain differentiation, was visualized with thickness-based surface color mapping. A closer view was obtained of the unique and complicated differentiation of the rhombencephalon, especially with regard to the internal view and thickening of the brain tissue. The present data contribute to a better understanding of brain and cerebral ventricle development.

Cochlear cytogenesis visualized through pulse labeling of chick embryos in culture.

Cytogenesis in the basilar papilla sensory epithelium of the chicken was investigated through pulse labeling of proliferative cells. Tritiated-thymidine was injected intravenously in chick embryos cultured in petri dishes. All embryos received the injection on the seventh day of incubation (E7), when the progenitors of hair cells and supporting cells are replicating deoxyribonucleic acid (DNA). Cells that were in the synthesis phase of the cell cycle, either at the time of the 3H-thymidine pulse or within 2 hours, incorporated detectable levels of the radioactive DNA precursor. Labeled cells were identified in cochleae from embryos fixed at 0.5, 1, 2, 4, 6, 12 hours, 6 and 8 days after the pulse. One hour after the injection the majority of labeled nuclei were in the basal and middle strata of the sensory epithelium. Four to 6 hours after the injection, a greater number of labeled cells appeared in the lumenal stratum. The patterns of labeled cells in embryos fixed immediately after the injection of 3H-thymidine and in others fixed 6 to 8 days after the injection were unchanged, suggesting that the progenitor cells divide and their progeny differentiate in the sensory epithelium without appreciable transverse migration. Mitotic figures were usually observed only in the lumenal stratum. Analysis of DNA content in the populations of Feulgen-stained nuclei at three levels of depth through the epithelium also produced results consistent with the conclusion that vertical nuclear migration occurs during development of the cells in this sensory epithelium.

Cell production in the chicken cochlea.

In the chicken cochlea, the structural features of the cilia bundles of individual hair cells vary systematically along the length of the sensory epithelium. As a first approach to understanding the developmental mechanisms that underlie this precise arrangement of structurally distinct hair cells, the spatiotemporal pattern of the terminal mitoses of their precursor cells was investigated by administering 3H-thymidine, a radioactive precursor to DNA. This demonstrated that the first hair cells were produced during the sixth day of incubation and formed a longitudinal band that extended along most of the length of the sensory epithelium. The epithelium grew further through appositional addition of hair cells at the edges of this first band of cells, and the hair cell addition process expanded into the surrounding areas during the next 3 days. By the ninth day of incubation all the hair cells in the sensory epithelium except for those at the peripheral edges in the distal (apex) portion had been produced through terminal mitoses. Our results have demonstrated that hair cells that have similar stereocilia phenotypes do not all leave the mitotic cycle at the same time.

A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 1. Construction of the basic framework.

A novel class of potent, selective, and orally active non-peptide bradykinin (BK) B2 receptor antagonists were designed and synthesized starting from 8-benzyloxyimidazo[1,2-a]pyridine derivative 2. The unique screening lead (2) was discovered by a two-step intentional random screening process, involving recognition of the relationship between BK and angiotensin II (Ang II) and the common structural features. Systematic chemical modification of 2 elucidated the structural requirements essential for B2 binding affinity leading to the identification of 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo- 2- methylimidazo[1,2-a]pyridine skeleton as the basic framework of this new series of B2 antagonists. A molecular modeling study suggested the key role of the N-methylanilide moiety at the 3-position of the 2,6-dichlorobenzene ring to allow these compounds to adopt the characteristic active conformation. The representative lead compounds inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors, with nanomolar IC50S and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea pigs at an oral dose of 1 mg/kg. Pharmacokinetic studies of compounds 47c and 50b in rats highlighted their excellent oral bioavailabilities, indicating that they represent the first orally active non-peptide B2 antagonists reported to date.

The identification of an orally active, nonpeptide bradykinin B2 receptor antagonist, FR173657.

1. An orally active, nonpeptide bradykinin (BK) B2 receptor antagonist, FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2-4-dichloro-3-[(2-methyl-8-quinolin yl) oxymethyl]phenyl]-N-methylaminocarbonyl-methyl] acrylamide) has been identified. 2. This compound displaced [3H]-BK binding to B2 receptors present in guinea-pig ileum membranes with an IC50 of 5.6 x 10(-10) M and in rat uterus with an IC50 of 1.5 x 10(-9) M. It did not inhibit different specific radio-ligand binding to other receptor sites. 3. In human lung fibroblast IMR-90 cells, FR173657 displaced [3H]-BK binding to B2 receptors with an IC50 of 2.9 x 10(-9) M and a Ki of 3.6 x 10(-10) M, but did not reduce [3H]-des]Arg10-kallidin binding to B1 receptors. 4. In guinea-pig isolated preparations, FR173657 antagonized BK-induced contractions with an IC50 of 7.9 x 10(-9) M, but did not antagonize acetylcholine or histamine-induced contractions even at a concentration of 10(-6) M. FR173657 caused parallel rightward shifts of the concentration-response curves to BK at concentrations of 10(-9) M and 3.2 x 10(-9) M, and a little depression of the maximal response in addition to the parallel rightward shift of the concentration-response curve at a concentration of 10(-8) M. Analysis of the data yield a pA2 of 9.2 +/- 0.2 (n = 5) and a slope of 1.5 +/- 0.2 (n = 5). 5. In vivo, the oral administration of FR173657 inhibited BK-induced bronchoconstriction dose-dependently in guinea-pigs with an ED50 of 0.075 mg kg-1, but did not inhibit histamine-induced bronchoconstriction even at 1 mg kg-1. FR173657 also inhibited carrageenin-induced paw oedema with an ED50 of 6.8 mg kg-1 2 h after the carrageenin injection in rats. 6. These results show that FR173657 is a potent, selective, and orally active bradykinin B2 receptor antagonist.

More than 1,000 cases of total parathyroidectomy with forearm autograft for renal hyperparathyroidism.

Between March 1981 and December 2000, we performed 1,053 total parathyroidectomies with forearm autograft for advanced renal hyperparathyroidism (HPT). Based on histopathologic and pathophysiologic investigations, surgical treatment should be considered when parathyroid glands show nodular hyperplasia. Measuring parathyroid volume by ultrasonography was useful to detect nodular glands and to determine surgical indications. The clinical effect of parathyroidectomy on the symptoms and biochemical variables was striking. Skeletal deformity, progressive bone loss, and vessel calcification leading to high mortality risk could not be alleviated by even successful surgery, however. To prevent cardiovascular complications, parathyroidectomy should be performed in the relatively early stage of renal HPT. Total parathyroidectomy with forearm autograft is a suitable procedure for renal HPT, especially in patients who require long-term hemodialysis. For surgeons, it is important to remove all parathyroid glands, including supernumerary glands, at the initial operation and to choose adequate parathyroid tissue for the autograft to prevent persistent and recurrent HPT. Although the risk of graft-dependent recurrent HPT is not negligible, enlarged transplanted parathyroid tissue can be removed easily and noninvasively from the forearm under local anesthesia. There is no risk of hypofunction of the autograft.

Osteoprotegerin levels before and after renal transplantation.

Osteoprotegerin (OPG) is a newly identified glycoprotein that belongs to the tumor necrosis factor receptor superfamily and regulates bone mass by inhibiting osteoclastic bone resorption. The regulatory mechanism of OPG is still unclear after successful renal transplantation (RTX), however, resulting in resolution of uremia. The present study was designed to clarify the potential role of OPG in uremia and after RTX under immunosuppressive therapy. We evaluated circulating OPG levels by measuring them before and after RTX (postoperative days 2, 14, and 28). Our protocol of immunosuppressive drugs was dual therapy using cyclosporine and steroids. Serum OPG was quantitated using enzyme-linked immunosorbent assay. After successful RTX, serum OPG levels decreased significantly on day 14 and day 28 compared with the baseline level (P < 0.05). Creatinine clearance dramatically increased until day 14 and decreased thereafter. Serum OPG declines for the first 2 weeks after RTX owing to functioning allograft and decreases again for the next 2 weeks because of steroids and possible immunosuppressive agents.

Ethnic or environmental differences in disparate geographic regions may influence the histology of flat colorectal neoplasias.

Histologic sections of endoscopically flat colorectal polyps removed in Tokyo and Stockholm were reviewed. A total of 178 flat colorectal neoplasias (88 from the Tokyo Medical College Hospital, Tokyo and 90 from the Karolinska Hospital, Stockholm) were classified following strict histologic criteria by two different pathologists (one Swedish and the other Japanese). The number of polyps with high grade dysplasia, with intramucosal carcinoma and with invasive carcinoma were significantly higher (p < 0.001) in Tokyo (61.4% or 54/88) than in Stockholm (15.0% or 14/90). The present results suggest that flat colorectal neoplasic polyps may be histologically more "severe" and more "aggressive" in Japanese than in Swedish patients. The possibility that more "advanced" lesions had been inadvertently removed in Tokyo was discounted as Japanese endoscopists were also instrumental in excising many of the flat colorectal polyps in Stockholm. Ethnic and/or environmental differences seem to play a crucial role in the evolution of flat colorectal neoplasic polyps from LGD and HGD, to intramucosal and to invasive carcinoma.

Non-polypoid colorectal neoplasias: a multicentric study.

A total of 781 non-polypoid colorectal neoplasias harvested at 4 main Hospitals in Tokyo, Japan (n = 420) and at 4 different time-intervals at the Karolinska Hospital, Stockholm, Sweden (n = 361) were reviewed. By applying strict histologic definitions, the lesions were classified into adenomas with low grade dysplasia (LGD), with high grade dysplasia (HGD), intramucosal carcinomas (IMC) or submucosal carcinomas (SMC). Of the non-polypoid neoplastic lesions reviewed in Sweden, 82.8% (n = 299) had LGD. In Japanese patients only 42.6% (n = 179) had LGD (p < or = 0.001). On the other hand, as many as 42.4% (n = 178) of the non-polypoid lesions in Japanese patients had HGD, but only 14.1% (n = 51) of those in Swedish patients (p < or = 0.001). Whereas 15.0% (n = 63) of the non-polypoid neoplasias seen in Japan were IMC or SMC, only 3.0% (n = 11) of those seen in Sweden were IMC or SMC (p < or = 0.001). The cause(s) for these differences remains unclear. In Japan, however, a marked increased incidence of colonic cancer has been recorded in later years. Whether the "catching up phenomenon" by the Japanese with western colonic cancer incidence includes increased histologic aggressiveness of non-polypoid neoplastic polyps--as found in this survey--remains to be elucidated.

Changes in coagulation condition, cytokine, adhesion molecule after repair of type A aortic dissection.

OBJECTIVE: Because residual dissection often exists even after the repair of a type A dissection, we evaluated coagulation conditions, cytokine levels, and adhesion molecule levels in mid-term follow up after repair of type A dissections. METHODS: Thrombin-antithrombin III complex (TAT), D-dimer, soluble interleukin-2 receptor (sIL-2R), soluble intercellular adhesion molecule (sICAM)-1, and type III procollagen peptide (PIIIP) were measured in 12 patients (mean age=63 years) following the repair of a type A aortic dissection at 6-82 months after repair (median=33 months). RESULTS: In the chronic phase, TAT and D-dimer were significantly higher in patients following the repair of a type A dissection compared to healthy controls (TAT; 12+/-8 vs. 2.5+/-1.2 ng/ml, P = 0.0001, D-dimer; 779+/-1384 vs. 104+/-46 U/ml, P = 0.0001). Cytokine was significantly higher in the affected patients (sIL-2R; 556+/-205 vs. 398+/-132 U/ml, P = 0.003, sICAM-1; 255+/-131 vs. 211+/-48 ng/ml, P = 0.136). Collagen turnover (PIIIP) showed a significantly higher value in the affected patients (0.80+/-0.32, vs. 0.58+/-0.13 U/ml, P = 0.002). sIL-2R, sICAM-1 and PIIIP showed a negative correlation with the follow-up period (sIL-2R; r = -0.733, P = 0.0067, sICAM-1; r = -0.61, P = 0.035, PIIIP; r = -0.692, P = 0.0126). We found a positive correlation between aortic size and TAT (r = 0.644, P = 0.0238, n = 12) as well as with D-dimer (r = -0.7831, P = 0.0106, n = 12) and TAT showed significantly higher values in the residual dissection group compared to those without residual dissection (16.6+/-7.9 vs. 7.45+/-4.75 ng/ml, P = 0.035). CONCLUSION: Hypercoagulation conditions continued even after repair. Both TAT and D-dimer would be good indices for following up patients having repaired aortic dissections. Furthermore, cytokine, adhesion molecules, and collagen turnover would return to a stable state unless impairment and expansion of the vessel wall occurred.