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Chordomas are rare tumors of the axial skeleton that are refractory to conventional therapy. Few studies have compared the morphological and molecular characteristics of chordomas according to the skull base and sacral locations. Histopathological data and changes revealed by array comparative genomic hybridization (CGH) and next-generation sequencing (NGS) of cell cycle regulation genes were analyzed for 28 skull base (SBCs) and 15 sacral (SC) chordomas. All cases were conventional chordomas. SBCs were significantly more frequent in patients aged <40 years and SCs predominated in patients aged >60 years. Mitotic indices ≥2 mitoses/10 high-power fields were correlated with high degrees of nuclear atypia and Ki67 labeling indices ≥6%. We identified 321 genomic positions, and copy number variation losses were more frequent than gain. Moreover, we report a panel of 85 genetic variants of cell cycle genes and the presence of molecular clusters for chordoma as well in CGH as in NGS. These new data strengthen the view that the chordoma should not be considered as a single molecular entity., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Rhodiola sacra is a widely used pharmaceutical component with multiple functions, including anti-oxidation and anti-inflammation. However, the exact mechanisms involved in neuroprotection against transient global cerebral ischemia (tGCI) remain to be elucidated. Herein, we aim at closing the gap in understanding on whether rhodiola sacra reduces neuronal death in hippocampal CA1 and at demonstrating how rhodiola sacra offers neuroprotection after tGCI. Results: The results show that rhodiola sacra (2.4 g/kg/d by feeding) pretreatment or/and postreatment significantly alleviated neuronal injury, inhibited glial activation, and improved cognitive function in male rats subjected to tGCI. The neuroprotection of prophylaxis with rhodiola sacra is equivalent to that of therapeutics. The binding mode of adenosine monophosphate-activated protein kinase (AMPK) α2-subunit with rhodiola sacra was predicted by molecular docking. Further, rhodiola sacra upregulates phosphorylated AMPK and promotes nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2). In addition, rhodiola sacra increases heme oxygenase-1 (HO-1) expression and activity and reduces malondialdehyde (MDA) content in CA1 after tGCI. However, the neuroprotection of rhodiola sacra is abolished by Nrf2 knockdown with small interfering RNA (siRNA) after tGCI. Similarly, the inhibition of AMPK with Compound C or siRNA against AMPK α2 aggravates neuronal death after tGCI through decreasing nuclear Nrf2 and the expression and activity of HO-1, and by increasing the release of MDA. Innovation and Conclusion: For the first time, this study demonstrates that as a prophylactic or therapeutic agent rhodiola sacra prevents oxidant stress, protects neurons, and improves cognitive function through activating the AMPK/Nrf2 pathway in tGCI rats. Antioxid. Redox Signal . 36, 567-591.

Storage and voiding of urine from the lower urinary tract (LUT) must be timed precisely to occur in appropriate behavioral contexts. A major part of the CNS circuit that coordinates this activity is found in the lumbosacral spinal cord. Immediate early gene (IEG) activity mapping has been widely used to investigate the lumbosacral LUT-related circuit, but most reports focus on the effects of noxious stimulation in anesthetized female rats. Here we use c-Fos and EGR-1 (Zif268) activity mapping of lumbosacral spinal cord to investigate cystometry-induced micturition in awake female and male rats. In females, after cystometry c-Fos neurons in spinal cord segments L5-S2 were concentrated in the sacral parasympathetic nucleus (SPN), dorsal horn laminae II-IV, and dorsal commissural nucleus (SDCom). Comparisons of cystometry and control groups in male and female revealed sex differences. Activity mapping suggested dorsal horn laminae II-IV was activated in females but showed net inhibition in males. However, inhibition in male rats was not detected by EGR-1 activity mapping, which showed low coexpression with c-Fos. A class of catecholamine neurons in SPN and SDCom neurons were also more strongly activated by micturition in females. In both sexes, most c-Fos neurons were identified as excitatory by their absence of Pax2 expression. In conclusion, IEG mapping in awake male and female rats has extended our understanding of the functional molecular anatomy of the LUT-related circuit in spinal cord. Using this approach, we have identified sex differences that were not detected by previous studies in anesthetized rats., (© 2020 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals, Inc.)

Background: Despite being non-life threatening, uterine prolapse is a reproductive health problem that interferes psychosocial life, economical and sexual function. Uterine prolapse can be caused by direct trauma resulting in damaged and weakened levator ani muscle which in turn causing sacrouterine ligament to stretch in order to maintain uterus normal position. The main component of sacrouterine ligament is collagen. Types of collagen that was involved in the occurrence of uterine prolapse are which plays a role of risk of occurrence uterine prolapse is collagen type-1 and type-3. Collagen type-1 has a good resistance and flexible to strain. If there is a disruption in the expression of collagen in sacrouterine ligament, it will result in cause uterine prolapse., Objective: The aim of this study is to prove low expression of collagen type-1 in sacrouterine ligament is a risk factor for the occurrence of stage III-IV uterine prolapse., Study Design: This study was an observational study using case-control approach. A total of 22 cases of stage III-IV uterine prolapse and 22 cases of non-uterine prolapse as control group were selected by consecutive sampling. This study was carried out in Sanglah General Hospital and Pathobiology Laboratory of Veterinary Faculty of Udayana. Samples were taken from sacrouterine ligament of individual with stage III-IV uterine prolapse compared to non-prolapse uterine who had undergone total hysterectomy., Results: Chi-square analysis with 95 % confidence interval indicated that low expression of collagen type-1 was 6 times more likely to be the risk factor of stage III-IV uterine prolapse (OR = 5.95; 95 %CI = 1.59-22.33; p = 0.006)., Conclusion: Low collagen type-1 in sacrouterine ligament is a risk factor of stage III-IV uterine prolapse., (Copyright © 2020. Published by Elsevier B.V.)

Introduction and Hypothesis: Abnormalities of connective tissue structure or its repair mechanism may predispose women to pelvic organ prolapse (POP). We hypothesized that the expression of tenascin-X in the uterosacral ligament of postmenopausal women with symptomatic POP is increased compared with postmenopausal women without POP. Furthermore, we identified clinical risk factors associated with POP in our study population., Methods: We conducted a retrospective case-control study in which 33 postmenopausal women with symptomatic POP ≥ pelvic organ prolapse quantification system (POP-Q) stage II were matched with 33 postmenopausal women without POP. Studied tissue specimens were taken from hysterectomy specimens, and tenascin-X expression was investigated by immunohistochemistry. The immunohistochemical profile of the uterosacral connective tissue of cases and controls was compared., Results: Tenascin-X was expressed in 94% of POP cases and in 91% of controls. Our study failed to show any statistically significant differences in tenascin-X expression between women with and without POP (p = 0.64). However, tenascin-X was significantly more expressed in cases with severe prolapse (POP-Q stage IV) compared with moderate prolapse stages (POP-Q stage II and III) (p = 0.001). Advanced patient age as well as early menopausal age remained independent risk factors associated with POP in multiple logistic regression analysis (p = 0.001)., Conclusion: No difference could be demonstrated between tenascin-X expression in patients with or without POP. Tenascin-X does not seem to play a major role in the pathogenesis of POP in postmenopausal women.

The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end of the spine. Outflow of CSF tracers from the spinal subarachnoid space occurred predominantly from intravertebral regions of the sacral spine to lymphatic vessels, leading to sacral and iliac LNs. Clearance of CSF from the spine to lymphatic vessels may have significance for many conditions, including multiple sclerosis and spinal cord injury., (© 2019 Ma et al.)

Bone tracer uptake related to ureteral stones has been reported several times before. We present a right ureteral stone mimicking abnormal focal sacral uptake on planar scan in a patient with rectal cancer. This case highlights the necessity of performing SPECT/CT to ascertain the origin of abnormal focal sacral uptake on planar scan, especially in patients with a history of kidney stones.

The ADAM (A Disintegrin and Metalloprotease) is a zinc-dependent family of transmembrane proteins upregulated in cancers. As the most frequent member, ADAM10's potential prognostic role in chordoma is unknown., Objective: We investigated the expression of ADAM10 protein and its prognostic value in sacral chordoma., Design: Clinical information of patients with sacral chordoma diagnosis during a 7-year period and their archived pathology were retrieved. Immunohistochemistry study of the expression of ADAM10 protein in sacral chordoma and control samples was conducted. The ADAM10 expression was correlated with the patients' clinicopathological information and analyzed by statistical methods., Results: The average age of 64 patients was 57.6 years (range, 35-83 years). Follow-up ranged from 12 to 141 months (mean, 72 months). The histological type included 47 classic, 6 chondroid, and 11 dedifferentiated chordomas. The expression level of ADAM10 was significantly correlated with the histological type ( χ 2 =11.345, P =0.003), metastasis ( χ 2 =10.149, P =0.001), overall survival (log-rank test: χ 2 =8.177, P =0.004) and disease free survival (log-rank test: χ 2 =6.805, P =0.009). The average survival time of patients with weak expression of ADAM10 was longer than that of strong expression., Conclusion: The expression of ADAM10 protein is related to the histologic type and the prognosis of sacral chordoma., (© 2019 by the Association of Clinical Scientists, Inc.)

Pelvic organ prolapse (POP) is an increasingly serious health problem that impairs quality of life and is caused by multiple additive genetic and environmental factors. As the uterosacral ligaments (ULs) provide primary support for the pelvic organs, it was hypothesized that disruption of these ligaments (as a result of aberrant methylation) may lead to a loss of support and eventually contribute to POP. In the present study, whether there are any aberrant methylations in the ULs of patients with POP compared to those of controls was investigated. Genomic DNA was isolated from the ULs of five women with POP and four women without POP, as controls, undergoing hysterectomy for benign conditions. An Illumina Infinium Methylation EPICBeadChips Infinium Human Methylation 850 K bead array was used to investigate the total methylation in the ULs. There were 3,723 differentially methylated CpG sites (Δβ<0.14; P<0.05), including 3,576 hypermethylation and 147 hypomethylation sites in the ULs of patients with POP compared with the normal controls. There were more hypermethylated CpG sites, but a high ratio of hypomethylation between CpG islands and the N‑shelf; in the gene structure, there was more hypermethylation than hypomethylation in TSS1500 and the 5' untranslated region. Gene ontology analysis demonstrated that these differentially methylated genes were associated with 'cell morphogenesis', 'extracellular matrix', 'cell junction', 'protein binding' and 'guanosine triphosphatase activity'. Several significant pathways were identified, including 'focal adhesion' and 'extracellular matrix‑receptor interaction pathway'. This study provides evidence that there are differences in genome‑wide DNA methylation between ULs in menopausal women with and without POP, and that epigenetic mechanisms may partly contribute to POP pathogenesis.

Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an α6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis. DDR to IR in U-CH1 cells was compared to normal prostate epithelial (PrEC) and tumor cells (DU145). Flow cytometry showed a dose- and time-dependent increase in γH2AX and pKAP1 expression in all cell lines. However, nearly 50% of U-CH1 cells exhibited nonresponsive phenotype to IR (measured by γH2AX and pKAP1) independent of cell cycle status. Immunofluorescence microscopy verified that only 15% of U-CH1 clustered cells were γH2AX or pKAP1 positive (versus 80% of nonclustered cells) 2 hours following 2-Gy IR. Conversely, both tumor cell lines were uniformly defective in pATM response. HYD1, a synthetic ECM ligand, inhibited DDR through an unresolved γH2AX response. β1 integrin-blocking antibody (AIIB2) decreased cell survival 50% itself and approximately doubled the IR-induced cell kill at all IR doses observed at 2 and 4 weeks posttreatment. These results suggest that a heterogeneity of DDR to IR exists within a chordoma population. Blocking integrin function alone and/or as an adjuvant to IR may eradicate chordomas containing the cohesive cluster phenotype., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The far upstream element (FUSE)-binding protein 1 (FUBP1), a well-known transcriptional regulator of the proto-oncogene c-Myc, has been demonstrated by previous work to be aberrantly expressed in a variety of tumors and plays a critical role in tumor progression; however, its expression and function in relatively rare and aggressive chordomas remains unclear. In this retrospective study, we reviewed clinicopathologic characteristics of 40 patients diagnosed with sacral chordoma, and analyzed 40 tumor and 20 distant normal tissues obtained from patients during the primary surgical tumor excision. Using immunohistochemistry, we observed an up-regulation in the expression of FUBP1 and c-Myc in sacral chordomas compared with the normal tissues (P = 0.001 for both). Additionally, positive correlations of FUBP1 expression with c-Myc (γ = 0.651, P < 0.001) and the cell proliferation index Ki-67 expression (γ = 0.447, P = 0.004) were indicated using Spearman's rank correlation coefficient. Increased expression of FUBP1 was significantly associated with tumor invasion into the surrounding muscles (P = 0.002). Kaplan-Meier curves demonstrated the association between FUBP1 levels and the patients' local recurrence-free survival (LRFS) (P < 0.001) but not with the overall survival (OS) (P = 0.070). The independent prognostic significance of FUBP1 levels for the LRFS was indicated by multivariate analysis (HR = 4.272; 95% CI, 1.133-16.112; P = 0.032). Our findings demonstrate an association between FUBP1 levels and chordoma progression and prognosis, suggesting that FUBP1 can be used as a biomarker and a potential therapeutic target., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Pelvic organ prolapse (POP) is a major health problem that impairs the quality of life with a wide clinical spectrum. Since the uterosacral ligaments provide primary support for the uterus and the upper vagina, we hypothesize that the disruption of these ligaments may lead to a loss of support and eventually contribute to POP., Design and Methods: In this study, we therefore investigated whether there are any differences in the transcription profile of uterosacral ligaments in patients with POP when compared to those of the control samples. Seventeen women with POP and 8 non-POP controls undergoing hysterectomy for benign conditions were included in the study. Affymetrix® Gene Chip microarrays (Human Hu 133 plus 2.0) were used for whole genome gene expression profiling analysis., Results: There was 1 significantly down-regulated gene, NKX2-3 in patients with POP compared to the controls (p=4.28464e-013). KIF11 gene was found to be significantly down-regulated in patients with ≥3 deliveries compared to patients with <3 deliveries (p=0.0156237). UGT1A1 (p=2.43388e-005), SCARB1 (p=1.19001e-006) and NKX2-3 (p=2.17966e-013) genes were found to be significantly down-regulated in the premenopausal patients compared to the premenopausal controls. UGT1A1 gene was also found to be significantly down-regulated in the post menopausal patients compared to the postmenopausal controls (p=0.0005)., Conclusion: This study provides evidence for a significant down-regulation of the genes that take role in cell cycle, proliferation and embryonic development along with cell adhesion process on the development of POP for the first time., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

To examine how the median sacral artery (MSA) is involved with the coccygeal body or glomus coccygeum, we studied serial frontal or sagittal sections of 14 embryos (approximately 5-6 weeks of gestation) and 12 fetuses (10-18 weeks). At five weeks, the caudal end of the dorsal aorta (i.e., MSA) accompanied putative sympathetic ganglion cells in front of the upper coccygeal and lower sacral vertebrae. At six weeks, a candidate for the initial coccygeal body was identified as a longitudinal arterial plexus involving nerve fibers and sympathetic ganglion cells between arteries. At 10-18 weeks, the MSA exhibited a highly tortuous course at the lower sacral and coccygeal levels, and was attached to and surrounded by veins, nerve fibers, and sympathetic ganglion cells near and between the bilateral origins of the levator ani muscle. Immunohistochemistry demonstrated expression of tyrosine hydroxylase and chromogranin A in the nerves. However, throughout the stages examined, we found no evidence suggestive of an arteriovenous anastomosis, such as well-developed smooth muscle. An acute anterior flexure of the vertebrae at the lower sacrum, as well as regression of the secondary neural tube, seemed to induce arterial plexus formation from an initial straight MSA. Nerves and ganglion cells were likely to be secondarily involved with the plexus because of the close topographical relationship. However, these nerves might play a major role in the extreme change into adult morphology. An arteriovenous anastomosis along the MSA might be an overinterpretation, at least in the prenatal human. Anat Rec, 299:819-827, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Study Design: This is a retrospective, diagnostic study, level IV., Background: It appears to be necessary to identify prognostic markers for individual risk estimation for progression and survival in patients with chordoma, a rare disease. Are pre-operative serum levels of C-reactive protein (CRP) associated with disease progression and survival?, Methods: Survival rates of 24 patients (18 males, 6 females) (mean age 67 years (SD ± 16; range 20-85 years); minimum follow-up 2 years, mean follow-up 5 years (SD ± 5; range 2-19 years)) with chordoma of the lower spine and sacrum were assessed with a focus on pre-operative CRP levels., Results: The survival rate of patients with pre-operative CRP level of >1.0 mg/dl was lower than that of patients with a CRP level <1.0 mg/dl (p = 0.01). The estimated 10-year survival of patients with pre-operative CRP values <1.0 and >1.0 mg/dl was 76 and 25%, respectively. CRP remained as an independent survival factor (p = 0.025; CI 95% 1.0-2.6) in multivariable analysis., Conclusions: Pre-operative CRP levels appear to be a biomarker for disease-specific survival in patients with chordoma of the lumbar spine and sacrum. A validation of our finding with larger cohorts and integration of putative risk factor would further elucidate CRP a surrogate for tumor progression.

Background: Pelvic organ prolapse (POP) is a major health problem in adult women that involves many factors. No proteomic analysis has been conducted exclusively in POP patients. This study aimed to identify the differential expression of proteins that may be involved in POP by proteomic analysis., Methods: Samples of the uterosacral ligament (USL) were collected from five POP patients and five non-POP patients matched according to age, parity, and menopausal status and analyzed using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the mRNA expression of proteins that showed differential expression in the proteomic analyses., Results: Proteins differentially expressed between POP and non-POP patients were detected. Eight proteins that were down-regulated in the POP group were identified by MALDI-TOF-MS. These proteins included electron transfer flavoprotein, apolipoprotein A-I, actin, transgelin, cofilin-1, cyclophilin A, myosin, and galectin-1, and their expression was verified by qRT-PCR., Conclusion: Using comparative proteomics, we identified eight differentially expressed proteins (including four cytoskeleton proteins and three proteins related to apoptosis) in the USL that may be involved in apoptosis associated with the tissue effects in POP pathophysiology.

Background: Paragangliomas are derived from neurosecretory cells believed to be of neural crest origin. A spinal location of paraganglioma is rare and usually presents as an intradural mass., Patient and Methods: A primary intraosseous paraganglioma of sacrum is extremely unusual, and only 6 cases were reported. In this study, we report a rare case of a 44-year-old man with the complaint of low back pain and lower extremity weakness. Imaging workup, including computerized tomography (CT), and magnetic resonance imaging (MRI) presented an intraosseous sacral lesion with invasion of sacrum in the S1-S3 vertebrae, and extension to L4-L5 spinal canal. The patient underwent subtotal tumor resection, followed by radiation therapy., Results: The morphological and immunohistochemical studies revealed a composite tumor of paraganglioma and ganglioneuroma components, with immunopositivity for cytokeratin., Conclusions: To the best of our knowledge, this is the first report in the literature demonstrating an intraosseous sacral paraganglioma with these 2 pathological features.

Sacral chordoma is an aggressive bone tumor with a high local recurrence rate. Surgery remains the standard treatment because of its resistance to chemotherapy and radiotherapy. However, recurrence occurs frequently even after complete surgical resection. Great effort has been invested in discovering novel biomarkers and therapeutic targets. To date, the molecular mechanism is still unclear. In this study, we evaluated the expression of sphingosine kinase 1 (SPHK1) in 42 sacral chordoma samples and 16 distant normal tissue specimens by immunohistochemical staining. In addition, we analyzed its association with the clinical factors and patients' prognosis. Of all the chordoma samples, 69 % (29/42) showed high expression of SPHK1, whereas, only 19 % (3/16) of distant normal tissues expressed a high level of SPHK1 (p = 0.001). Chi-square analysis revealed that high expression of SPHK1 was significantly correlated with tumor recurrence (p = 0.019) and invasion into surrounding muscle (p = 0.005), while the data did not indicate any association with patients' gender, age, tumor location and size (p > 0.05). Kaplan-Meier survival curve and log-rank test showed that patients with high expression of SPHK1 possessed shorter continuous disease-free survival time. Conclusively, SPHK1 may become a potential biomarker for sacral chordoma in predicting its recurrence and patients' prognosis.

Background: Biodistribution data to date using In-ibritumomab tiuxetan have been initially obtained in patients with less than 25% lymphomatous bone marrow involvement and adequate hematopoietic synthetic function. In this article we present the results of an analysis of the biodistribution data obtained from a cohort of patients with extensive bone marrow involvement, baseline cytopenias, and chronic lymphocytic leukemia (CLL)., Materials and Methods: Thirty-nine patients with a diagnosis of B-cell lymphoma or CLL expressing the CD20 antigen, who had failed at least one prior regimen, and had evidence of persistent disease were included in this analysis; however, only 38 of them completed the treatment. Semiquantitative analysis of the biodistribution was performed using regions of interest over the liver, lungs, kidneys, spleen, and sacrum. The observed interpatient variability including higher liver uptake in four patients is discussed., Results: No severe solid organ toxicity was observed at the maximum administered activity of 1184 MBq (32 mCi) Y-ibritumomab tiuxetan. After accounting for differences in marrow involvement, patients with CLL exhibit comparable biodistributions to those with B-NHL. We found that the estimated sacral marrow uptake on 48 h images in patients with bone marrow involvement may be an indicator of bone marrow involvement. There was no correlation between tumor visualization and response to treatment., Conclusion: These data suggest that the imaging step is not critical when the administered activity is below 1184 MBq (32 mCi). However, our analysis confirms that the semiquantitative imaging data can be used to identify patients at risk for liver toxicity when higher doses of Y-ibritumomab tiuxetan are used. Patients with CLL can have excellent targeting of disease by In-ibritumomab tiuxetan, indicating potential efficacy in this patient population.

Objective: Pelvic organ prolapse (POP) is a major health concern for women. Its pathophysiology is yet not fully understood. We reported an impaired functional state of the smooth muscle compartment in uterosacral ligaments from patients with POP, which was cholinergic, stimulated by oxytocin and modulated by relaxin-2. The current study investigated the presence of oxytocin and relaxin-2 and their receptors in the uterosacral ligament from POP/non-POP patients., Design: Translational investigation on clinical samples., Setting: University hospital departments., Population and Samples: Fourty-three samples of uterosacral ligament from pre-menopausal patients with (n = 20) and without POP (n = 23)., Methods: Presence of relaxin-2, its receptors RXFP1 and RXFP2, and of oxytocin and its receptor were analysed by immunohistochemistry and classified using a staining score. Additionally, Western blot analysis was performed., Main Outcome Measures: Presence patterns with respect to POP and non-POP uterosacral ligament samples for pathophysiological understanding of POP., Results: Relaxin-2, oxytocin and their receptors were expressed in endothelial cells, the smooth muscle compartment and vasa vasorum in the arteries and veins of the uterosacral ligament, in the smooth muscle compartment present in the ground reticulum and in nerves running through the uterosacral ligament. The presence level of relaxin-2 was higher in the uterosacral ligament of the POP cohort (p < 0.001)., Conclusions: We demonstrated that relaxin-2 had an increased presence in uterosacral ligaments from patients with POP, suggesting a role of the relaxin system in the pathogenesis of POP and identifying the relaxin system as a potential therapeutic target for the pharmacological treatment of POP., (© 2014 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Chordomas are rare and indolent bone tumors that arise in the skull base and mobile spine. Distant metastases occur in >20% of cases, but morbidity and mortality are mainly related to local relapses that affect the majority of patients. Standard chemotherapy has modest activity, whereas new targeted therapies (alone or in combination) have some activity in controlling disease progression. However, the scarcity of preclinical models capable of testing in vivo responses to these therapies hampers the development of new medical strategies., Methods: In this study, 8 chordoma samples taken from 8 patients were implanted in nude mice. Four engrafted successfully and gave rise to tumor masses that were analyzed histologically, by means of fluorescence in situ hybridization and biochemical techniques. The data relating to each of the mouse tumors were compared with those obtained from the corresponding human tumor., Results: All 4 engraftments retained the histological, genetic and biochemical features of the human tumors they came from. In one epidermal growth factor receptor(EGFR)-positive xenograft, responsiveness to lapatinib was evaluated by comparing the pre- and post treatment findings. The treatment induced a low-level, heterogeneous switching off of EGFR and its downstream signaling effectors., Conclusions: Overall, this model is very close to human chordoma and represents a new means of undertaking preclinical investigations and developing tailored therapies.

Chordoma is a rare and invasive malignant tumor which primarily relies on surgical treatments. Anticipation of its recurrence and patient survival longevity has been a critical issue of the treatments. This retrospective study examined the survivin expression of sacral chordoma in 30 patients undergoing surgery in our hospital from January 2000 to July 2010, and compared it with chordoma recurrence. Survivin expression was 70 % positive in 30 patients. The positive expression of survivin with recurrence was significantly higher than that without recurrence (p = 0.017) and was inversely related to the continuous disease-free survival time (p < 0.001). Survivin expression was associated with recurrence. The correlation suggested that the survivin expression could be used as an independent predictor of recurrence and could be a potential bio-target gene of angiogenesis in sacral chordoma.

Aim: To determine the degree of CD40 overexpression in sacral chordomas and its correlation with tumor recurrence., Methods: CD40 or CD31 overexpression was determined by immunohistochemical staining; the microvessel density (MVD) was calculated according to the CD31 expression. The correlation of CD40 over-expression with tumor recurrence was analyzed., Results: 56% of the specimens from 36 cases of sacral chordomas overexpressed CD40, which is a significantly higher percentage than for the 2 specimens in 10 in normal notochordal tissue (p < 0.05). 36.84% of the specimens of the 19 recurrent cases were CD40 overexpressing, in contrast to less than 76.47% in the no-recurrence group (p < 0.05). Multivariate analysis demonstrated that CD40 overexpression and the resection margins were independent factors contributing to tumor recurrence. The MVD value was 25.71 ± 8.86 mm(-2) in the sacral chordomas and more than 6.63 ± 2.45 mm(-2) in the normal embryonic notochord tissue (p < 0.01). The MVD value in the recurrence group (30.08 ± 7.11 mm(-2)) was significantly higher than that of the no-recurrence group (20.82 ± 8.18 mm(-2); p < 0.05). But the MVD value was significantly lower in the CD40-overexpressing group than in the CD40-less expressing group (p < 0.05)., Conclusions: CD40 was overexpressed in sacral chordomas, and the overexpression was not dependent on the intratumoral MVD. CD40 overexpression was correlated with low recurrence of the tumor, implying that CD40 plays an important role in the antitumor response against sacral chordomas and in the inhibition of tumor recurrence., (© 2013 S. Karger GmbH, Freiburg)

The T-box transcription factor BRACHYURY (T) is a key regulator of mesoderm formation during early development. Complete loss of T has been shown to lead to embryonic lethality around E10.0. Here we characterize an inducible miRNA-based in vivo knockdown mouse model of T, termed KD3-T, which exhibits a hypomorphic phenotype. KD3-T embryos display axial skeletal defects caused by apoptosis of paraxial mesoderm, which is accompanied by urorectal malformations resembling the murine uro-recto-caudal syndrome and human caudal regression syndrome phenotypes. We show that there is a reduction of T in the notochord of KD3-T embryos which results in impaired notochord differentiation and its subsequent loss, whereas levels of T in the tailbud are sufficient for axis extension and patterning. Furthermore, the notochord in KD3-T embryos adopts a neural character and loses its ability to act as a signaling center. Since KD3-T animals survive until birth, they are useful for examining later roles for T in the development of urorectal tissues., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: Pelvic organ prolapse is associated with defects in connective tissues, including elastic fibers. The purpose of this study was to investigate the expression of fibulin-5 and lysyl oxidase-like 1 (LOXL1), which play an essential role in the synthesis and assembly of elastic fibers, in the uterosacral ligaments of women with advanced pelvic organ prolapse (POP) compared with controls., Method: Specimens were obtained prospectively during transvaginal or abdominal hysterectomy from 30 women with advanced pelvic organ prolapse and 30 controls matched to the POP group for age and parity among postmenopausal women with benign gynecologic diseases. The expressions of elastin, fibulin-5 and LOXL1 in uterosacral ligaments were measured by immunohistochemistry., Results: We detected a decreased, sometimes absent, expression of fibulin-5 and LOXL1 in the uterosacral ligaments of women with POP, despite a positive expression of elastin. There was a decrease in positive percentage of LOXL1 in the POP group (23.3%) compared with the controls (60%) (P = 0.004). With immunolabeling intensity classified as negative, weak, moderate or strong, there was a decrease in the expression of fibulin-5 in the POP group (P = 0.049). We also detected a significantly decreased expression of LOXL1 in the POP group (P = 0.001)., Conclusions: There was decreased expression of fibulin-5 and LOXL1 in the uterosacral ligaments of patients with pelvic organ prolapse, while the elastin expression was equivalent, which may suggest the possibility of defects in elastic fiber remodeling in the postpartum period and contribute to POP., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Both vagal and sacral neural crest cells contribute to the enteric nervous system in the hindgut. Because it is difficult to visualize sacral crest cells independently of vagal crest, the nature and extent of the sacral crest contribution to the enteric nervous system are not well established in rodents. To overcome this problem we generated mice in which only the fluorescent protein-labeled sacral crest are present in the terminal colon. We found that sacral crest cells were associated with extrinsic nerve fibers. We investigated the source, time of appearance, and characteristics of the extrinsic nerve fibers found in the aganglionic colon. We observed that the pelvic ganglion neurons contributed a number of extrinsic fibers that travel within the hindgut between circular and longitudinal muscles and within the submucosa and serosa. Sacral crest-derived cells along these fibers diminished in number from fetal to postnatal stages. A small number of sacral crest-derived cells were found between the muscle layers and expressed the neuronal marker Hu. We conclude that sacral crest cells enter the hindgut by advancing on extrinsic fibers and, in aganglionic preparations, they form a small number of neurons at sites normally occupied by myenteric ganglia. We also examined the colons of ganglionated preparations and found sacral crest-derived cells associated with both extrinsic nerve fibers and nascent ganglia. Extrinsic nerve fibers serve as a route of entry for both rodent and avian sacral crest into the hindgut., (Copyright © 2011 Wiley-Liss, Inc.)

Transient receptor potential vanilloid 1 (TRPV1), neurokinin 1 (NK1) receptor and substance P (SP) immunoreactivity (-ir) and mRNA in the rat lumbosacral spinal cord and urinary bladder were measured 24h after s.c. injection of the vanilloids, capsaicin (50mg/kg) and resiniferatoxin (RTX, 100μg/kg), or vehicle (10% ethanol/10% Tween 80/saline). In the spinal cord, capsaicin significantly reduced TRPV1 and SP-ir (40-45%) in laminae I/II compared to controls, while RTX produced decreases of ~35%. NK1-ir in the spinal cord was unaffected by both vanilloid treatments. In the bladder, SP-ir was reduced in urothelial cells of some capsaicin- and RTX-treated rats, while SP-ir in the suburothelium and muscularis was significantly reduced by RTX. A significant increase in NK1-ir was observed in the urothelium and muscularis after capsaicin administration. Capsaicin significantly increased SP mRNA in the spinal cord, and TRPV1 and SP mRNA in the bladder, whereas RTX increased TRPV1, SP and NK1 mRNA in the spinal cord, and TRPV1 and SP mRNA in the bladder. These data suggest that stimulation of TRPV1 by low dose vanilloid administration can rapidly (within 24h) alter both transcription and translation of TRPV1 channels, SP and NK1 receptors in the rat urinary bladder and spinal cord., (2011 Elsevier B.V. All rights reserved.)

Objective: To compare the expression of collagen type I and matrix metalloproteinase-1 (MMP-1) in uterosacral ligament biopsies from women with and without pelvic organ prolapse (POP)., Study Design: Uterosacral ligament biopsies were obtained from women with POP (n=46) and control subjects (n=49). Immunohistochemistry for collagen type I and MMP-1 was performed on formalin-fixed and paraffin-embedded sections. The two groups were matched for age, body mass index, parity and postmenopausal status. Statistical Package for the Social Sciences Version 13.0 was used for statistical analysis., Results: The expression of collagen type I (p=0.034) and MMP-1 (p=0.038) differed between women with POP and control subjects. There was increased expression of MMP-1 and decreased expression of collagen type 1 in uterosacral ligaments of women with POP compared with control subjects., Conclusions: This difference indicates a possible relationship between POP and the immunohistochemical expression of collagen type I and MMP-1 in uterosacral ligaments., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Sacral chordoma is a vessel-rich and infiltrative tumor, but the fundamental knowledge of its biological behavior remains unknown. This study was designed to investigate the expression levels and contributions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in the angiogenesis and recurrence of sacral chordoma and their correlations. An immunohistochemical method was used to investigate the expression of VEGF, MMP-9, and microvascular density (MVD) in 36 patients with sacral chordoma. Their differences in expressions were statistically analyzed and their correlations with angiogenesis and recurrence were evaluated. The mean MVD of sacral chordomas was significantly higher than that of the adjacent normal tissues (P = 0.033). Immunoreactivity for VEGF and MMP-9 was significantly higher in sacral chordoma tissues than in adjacent normal tissues (P = 0.008, P = 0.005). The mean MVD of VEGF and MMP-9 were statistically higher in positive group than in negative group (P = 0.015, P = 0.004), respectively . Moreover, a significant correlation was found between the VEGF and MMP-9 (P = 0.002). The log-rank test revealed that continuous disease-free survival time (CDFS) was significantly shorter in the MMP-9-positive group than in the MMP-9-negative group (P = 0.019), but the difference in the VEGF-positive group and the VEGF-negative group was not statistically significant (P = 0.938). Our data suggest that VEGF and MMP-9 might act with a synergistic effect and can positively regulate the angiogenesis in sacral chordoma. Positive expression of MMP-9 might indicate the local recurrence of sacral chordoma. The result suggests that some specific drugs which inhibit VEGF, MMP-9, or their receptors may have a good therapeutic effect for sacral chordoma.

Purpose: To compare fibulin-3 (FIB-3) and fibulin-5 (FIB-5) expressions in uterosacral ligaments (USL) of women with and without uterine prolapse., Study Design: USL were sampled in a standardized fashion from women with (n = 8) or without (n = 8) uterine prolapse. Quantitative Real-Time PCR was performed to measure mRNA and immunohistochemistry to assess protein expression., Results: FIB-3 mRNA expression and FIB-3 staining intensity was similar in the USL of women with and without uterine prolapse {[(FIB-3 mean +/- SD mRNA relative units) 0.45 +/- 0.41 vs. 0.46 +/- 0.82, NS] and [Intensity score, median (range), 1(0-1) vs. 1(0-1), NS]}. Both FIB-5 mRNA expression and FIB-5 staining intensity was significantly decreased in USL from women with uterine prolapse compared to women without prolapse {[(FIB-5 mean +/- SD mRNA relative units) 0.07 +/- 0.02 vs. 0.26 +/- 0.20, P = 0.02] and [Intensity score, median (range), 0(0-2) vs. 3(2-3), P = 0.002]}., Conclusion: FIB-5 expression is decreased in USL of women with uterine prolapse.

Purpose: The aim of this study was to evaluate the performance of (18)F-fluoride-PET/CT (PET/CT) for the diagnosis of sacroiliac joint (SIJ) arthritis in patients with active ankylosing spondylitis (AS)., Methods: Included in the study were 15 patients with AS according to the modified New York criteria (AS group) and with active disease and 13 patients with mechanical low back pain (MLBP; control group) who were investigated with whole-body (18)F-fluoride PET/CT. The ratio of the uptake in the SIJ and that in the sacrum (SIJ/S) was calculated for every joint., Results: The mean SIJ/S ratio of 30 quantified joints in the AS group was 1.66 (range 1.10-3.07) with PET/CT, and the mean SIJ/S ratio of 26 quantified joints in the MLBP group was 1.12 (range 0.71-1.52). The area under the receiver operating characteristic curve for SIJ arthritis was 0.84. With plain radiography as a the gold standard and taking an SIJ/S ratio of >1.3 as the threshold, the sensitivity, specificity and accuracy on a per patient basis were 80%, 77% and 79%, respectively. On a per SIJ basis, the greatest sensitivity (94%) was found in grade 3 sacroiliitis (n = 16)., Conclusion: Our results suggest that quantitative (18)F-fluoride PET/CT may play a role in the diagnosis of sacroiliitis in active AS and is an alternative to conventional bone scintigraphy in times of molybdenum shortage.

Background: It is very rare that gastrointestinal stromal tumor (GIST) occurs in the sacrum. Only one case of GIST occuring in the sacral region, with intracranial metastasis, has been reported in the literature. Moreover, only few cases have been published in literature about its clonal origin., Case Presentation: In this report, we present a rare case of GIST occuring in the sacrum and describe its clinicopathologic features, c-KIT gene mutation and clonal status. Microscopically, the lesion was composed of spindle cells arranged in cords, knitted and whirlpool patterns. Trabecula of bone were found in the lesion. The cytoplasm of tumor cells were abundant, and the nuclei were fusiform. Mitotic figures were rare. Immunohistochemically, the tumor cells showed positive reactivity for CD117 and CD34. On mutation analysis, a c-KIT gene mutation was found in exon 11. The result of clonal analysis demonstrated that the GIST was monoclonal., Conclusion: In summary, we showed that tumor material, phenotypically identical with GISTs was found in the sacrum. It is difficult to differentiate GISTs from other spindle cell tumors, hence the need for immunohistochemistry, the examination of c-KIT gene amplification and sequencing.

1. We previously demonstrated that p-chloroamphetamine (PCA) intravenously (i.v.) evokes a specific patterned bursting response in the vas deferens nerve (VDN) of anaesthetised male rats that is associated with contraction of the vas deferens, and ejaculation and contraction of the bulbospongiosus muscles. The present study used selective 5-HT agonists to induce similar rhythmic bursting responses in the VDN in order to reveal the 5-HT receptor subtypes involved. 2. The 5-HT(2C) receptor agonist (1.0 mg kg(-1) Ro600175 i.v.) evoked the characteristic bursting pattern responses in the VDN. The 5-HT(1A) receptor agonist (1.0 mg kg(-1) 8-OH-DPAT i.v.) failed to elicit any responses. However, 8-OH-DPAT coadministered in combination with Ro600175 induced a potentiation of the responses. 3. Responses were also evoked in rats with a mid-thoracic spinalisation, with a more predictable response being observed following the combination of agonists. This suggests an action of both agonists in the lumbosacral spinal cord. 4. Responses were blocked by 0.5 mg kg(-1) SB206553 i.v. (5-HT(2B/C) receptor antagonist) or 0.5 mg kg(-1) WAY100635 i.v. (5-HT(1A) receptor antagonist), but not 0.1 or 1.0 mg kg(-1) SB269970 i.v. (5-HT(7) receptor antagonist). 5. We suggest that activation of 5-HT(2C) and 5-HT(1A) receptor subtypes synergistically elicits contraction of the vas deferens through the activation of sympathetic preganglionic neurones in the spinal cord. 6. These data support the idea of a proejaculatory action of 5-HT(2C) receptors in the lumbosacral spinal cord, suggesting a descending 5-HT excitatory pathway in addition to a 5-HT inhibitory pathway. An excitatory action of 8-OH-DPAT at lumbosacral sites is also evident.

Objective: To compare tissue markers of collagen metabolism in the uterosacral ligaments with those in vaginal tissue in women with uterine prolapse., Design: Prospective observational experimental study., Setting: A tertiary urogynaecology unit., Population: Women referred for hysterectomy for prolapse or benign gynaecological disease., Methods: Matrix metalloproteinase (MMP)-2 and -9 expression, tissue inhibitors of metalloproteinase (TIMP)-2 expression and hydroxyproline content were measured in the uterosacral ligaments and vaginal tissue from 14 women with prolapse compared with 14 controls., Main Outcome Measures: Levels of MMP, TIMP and hydroxyproline in the uterosacral ligaments and vaginal tissue of women with prolapse and controls., Results: Fourteen women with prolapse and 14 women without prolapse (controls) were included. A significant increase in pro MMP-2 expression was seen in vaginal tissue from women with prolapse (P < 0.05) but not activated MMP-2, MMP-9 and TIMP-2. For uterosacral ligaments, the differences were not statistically significant. No significant difference in hydroxyproline content was found between control and prolapse in either tissue. Significant correlations exist in expression of pro-MMP-2, activated MMP-2, MMP-9 and TIMP-2 in vaginal tissue with that in uterosacral ligaments., Conclusions: Correlations existed between markers of collagen metabolism in the vaginal and uterosacral tissues. This suggests vaginal tissue reflects the endopelvic fascia. The changes which are more pronounced in vaginal tissue may be as a result of prolapse rather than cause.

Purpose: The purpose of this study was to reassess whether the Honda sign (HS) and its variants on bone scans can be used to differentiate an insufficiency fracture (IF) of the sacrum from a metastasis and to evaluate extrapelvic tracer accumulation in patients suspected of having a sacral IF., Methods and Materials: We retrospectively reviewed 34 bone scans of 26 patients suspected of having a sacral IF between January 1998 and June 2003., Results: Twenty-four of the patients had a sacral IF and 1 had a sacral metastasis from prostate cancer and another from lung cancer. The bone scans of only 15 (63%) of the 24 patients with a sacral IF exhibited the HS, 8 (33%) scans exhibited variants, and 4 (4%) scans showed whole-sacrum uptake. One of the 2 patients with metastasis exhibited the HS and the other exhibited a variant. The sensitivity and positive predictive value of HS plus its variants as diagnostic criteria for sacral IF were 96% and 92%, respectively. Seventeen patients (71%) had extrasacral accumulation. The most common site was the pubic bone (50%, 12 of 24), and the second most common site was the spine (46%, 11 of 24), where the accumulation was the result of a compression fracture or degenerative joint disease of the spine., Conclusions: A "Honda sign or variation" with evidence of fractures elsewhere or no evidence of other metastatic disease should be strong evidence for a sacral insufficiency fracture. The likelihood of having a solitary metastasis to the sacrum is small.

Study Design: Graded endplate injuries were performed in porcine lumbar discs. The effects of such injuries were compared to control animals in which a sham operation was performed., Objectives: To investigate the effects of endplate injuries on disc tissue., Summary of Background Data: Studies have shown that injuries of vertebral endplates are frequently found at autopsy. However, little is known on the effects of acute injuries of vertebral endplates in vivo., Methods: Ten domestic pigs were included in the study group. Under general anesthesia, the lower three discs of the lumbar spine were exposed and randomly submitted to multiple endplate injuries, isolated endplate injury, and no treatment. A sham operation was performed in 5 pigs used as control group. Animals were killed 7 months after surgery and the harvested lumbar spine submitted to MRI investigations, histologic, and biochemical analysis., Results: MRI showed that all but one discs treated with multiple endplate injuries were markedly degenerated while, of the discs treated with an isolated injury, one was markedly degenerated, five slightly degenerated and two were normal (P = 0.01). Histologic analysis showed severe changes in discs treated with multiple injuries. In those who had an isolated injury, changes were less severe and essentially limited to the posterior anulus or the inner anterior anulus. Biochemical analysis showed an inverse correlation between uronate content in the nucleus pulposus and severity of endplate injuries., Conclusions: Injuries of vertebral endplates in porcine discs were found to cause degenerative changes in the disc tissue on MRI, histologic, and biochemical investigations. The severity of such degenerative changes was related to the severity of endplate injuries. Injuries of vertebral endplate may be one of the pathomechanisms leading to early changes in the disc matrix and eventually to abnormal biomechanical behavior of the whole disc. The present animal model seems to be a suitable experimental model for disc degeneration.

The aim of this study was to determine the characteristics and clinical usefulness of 201Tl scintigraphy in giant-cell tumour of bone (GCT). Twenty-one patients with histopathologically proven benign GCT (22 lesions; 18 primary and four recurrent) underwent 201Tl scintigraphy. We also studied conventional osteosarcoma (10 lesions), a very common primary malignant bone tumour; and chordoma in the sacrum (four lesions), an entity requiring differential diagnosis from GCT of the sacrum. Early and delayed planar imaging was performed at 15 min (early) and 3 h (delayed) after the intravenous injection of 201Tl chloride (111 MBq). The Tl uptake ratio was calculated by dividing the count density of the tumour region of interest (ROI) by that of the background ROI. All GCT lesions showed increased Tl uptake in both early and delayed images. The mean Tl uptake ratios of primary GCT were 4.7 (range, 2.0-11.1) in the early images and 2.2 (range, 1.4-3.6) in the delayed images, and those of recurrent lesions were 5.8 (range, 2.4-11.5) in the early images and 2.7 (range, 2.0-4.3) in the delayed images. There were no significant differences between the uptake ratios in GCT and osteosarcoma, but the values of GCT tended to be higher than those of osteosarcoma, 3.1 (range, 1.7-4.4) in the early images and 1.8 (range, 1.3-2.3) in the delayed images. Chordoma did not show appreciable Tl uptake: the uptake ratio was 1.19 (range, 0.98-1.5) in the early images and 1.1 (range, 1.0-1.3) in the delayed images. In GCT, a benign lesion, Tl scintigraphy demonstrated marked uptake in both primary and recurrent lesions with no exceptions, precluding the use of Tl scintigraphy for the differential diagnosis of GCT from malignant tumours. However, the Tl scintigraphy can be used for excluding GCT when no lesional Tl uptake is observed, and diagnosing recurrent lesions on post-operative follow-up.

Objectives: To measure the thickness and cellularity of adult human sacral and iliac articular cartilages and the thickness and density of the subchondral bones., Methods: The right sacroiliac joints of 15 adult patients were examined post-mortem. HOME (Highly Optimized Microscope Environment) microscopy was used to measure articular cartilage and subchondral bone end-plate thickness. Conventional morphometric techniques were employed to estimate cartilage cellularity and cancellous bone density., Results: Sacral articular cartilage was thicker than iliac (1.81 vs 0.80 mm, P<0.001). Iliac cartilage cell density in all zones was higher than sacral. The overall mean was 31.19 x 10(-3) vs. 23.23 x 10(-3)/mm(3), P<0.001. Superficial zones contained more cells than middle and deep zones but there were large differences between the cell numbers of the middle and deep zones of both sacral and iliac cartilages. Iliac subchondral bone end-plates were thicker than sacral (0.36 vs 0.23 mm, P<0.001). The thickness of these plates was related inversely to that of the overlying articular cartilages. Iliac subchondral cancellous bone was twice as dense as sacral (22.07 vs. 12.05%, P<0.001), a ratio recognized anteriorly, centrally and posteriorly., Conclusions: Adult human sacral cartilage is thick and of low cell density. It rests upon a thin bone end-plate supported by porous, cancellous bone. Iliac cartilage and bone display the converse proportions. The identification of these variables may assist understanding of normal sacroiliac joint function and the interpretation of tissue changes in the spondylarthropathies.

We have investigated the projection patterns of peptidergic small-diameter primary afferent fibers to the cat sacrocaudal spinal cord, a region associated with midline structures of the lower urogenital system and of the tail. Calcitonin gene-related peptide (CGRP)-immunoreactive (CGRP-IR) primary afferent fibers were observed within the superficial laminae, rostrally as the typical inverted U-shaped band that capped the separate dorsal horns (S1 to rostral S2) and caudally as a broad band that spanned the entire mediolateral extent of the fused dorsal horns (caudal S2 and caudal). Within the dorsal gray commissure, labeling was seen as a periodic vertical, midline band. CGRP-IR labeling was prevalent in an extensive mediolateral distribution at the base of the dorsal horn, originating from both lateral and medial collateral bundles that extend from the superficial dorsal horn. Some bundles, in part traveling within the dorsal commissure, conspicuously crossed the midline. In addition to the robust projection to the superficial dorsal horn, there was a more extensive distribution of CGRP-IR fibers within the deeper portions of the cat sacrocaudal dorsal horn than has been reported for other regions of the cat spinal cord. Presumably, these deep projections convey visceral information to projection or segmental neurons at the neck of the dorsal horn and in the region of the central canal. This deep distribution overlaps the reported projections of the pelvic and pudendal nerves. In addition, the contralateral projections of CGRP-IR fibers may form an anatomical substrate of the bilateral receptive fields for selective dorsal horn neurons. The density and variety of CGRP-IR projection patterns is a reflection of the functional attributes of the innervated structures., (Copyright 2001 Wiley-Liss, Inc.)

Study Design: The proteoglycan metabolism of ovine disc nucleus pulposus and anulus fibrosus cells was investigated in relation to age, spinal level, and intrinsic spinal biomechanical properties., Objective: To evaluate the hypothesis that with aging loss of proteoglycans from the lumbosacral disc exceeds that from upper lumbar discs because of its proximity to a rigid segment, the sacrum., Summary of Background Data: The proteoglycan and associated water of the disc decreases with aging., Methods: Proteoglycans were extracted directly from the disc tissues using 4 M GuHCl and examined by composite agarose polyacrylamide gel electrophoresis. Disc cells were cultured in alginate beads, and their metabolic activity was assessed by 3H-thymidine incorporation into DNA and by bioreduction of a cell proliferation dye. Newly synthesized proteoglycans were radiolabeled with 35S, and their molecular weight distributions and ability to aggregate with hyaluronan were determined by Sephacryl S1000 gel chromatography. Resident proteoglycans extracted from disc tissues with 4 M GuHCl were similarly evaluated. A group of adult animals also were studied biomechanically to evaluate the range of spinal motion (L4/L5 to L7/S1)., Results: In contrast to the neonatal proteoglycan samples, the biosynthesis of proteoglycans by nucleus pulposus cells of adult discs increased progressively toward the sacrum. This correlated with increased metabolic activity. Analysis of the resident proteoglycans by composite agarose polyacrylamide gel electrophoresis indicated that although the aggrecan-1 population was present almost exclusively in the neonatal group, it was the aggrecan-2 population that predominated in the adult discs, and it became progressively more heterogeneous with aging and proximity of the disc to the sacrum., Conclusions: The proteoglycans of the lumbosacral disc of adult animals turned over faster than proteoglycans of adjacent lumbar discs. The reduced proteoglycan content and ability to aggregate, particularly in the nucleus pulposus of lumbosacral discs, indicated that proteoglycan catabolism exceeded the rate of biosynthesis. These events in the lumbosacral disc are thought to be determined mechanically by its proximity to the sacrum.

In this study the influence of soft-care systems on subcutaneous tissue pressure and pO2 has been examined. In 14 volunteers 3 probes were implanted over the os sacrum for measurement during the 20-minute periods. Then the probands were asked to lie on a standard mattress, on 8 static beds of various kind and on 3 dynamic soft-care systems. The clinical mattress pressure values amounted to 25.5 mm Hg (+/- 5.2; n = 14). The gell-cushion showed increased values (26.9 +/- 9.5 mm Hg; n = 5). Compared to the standard mattress the other systems showed reductions in pressure from 32.7% to 83.1%. The lowest pressure was recorded with an air-supported mattress (8.3 +/- 2.3 mm Hg; n = 5). The pO2 initial values before lying down varied greatly from individual to individual (26.9-71.3 mm Hg). In the course of the 20-minute periods the pO2 value sometimes remained constant, sometimes increased and at other times it decreased. Under extreme conditions (with 8 probands asked to lie on the floor) a correlation (r = -0.787) between pressure and pO2 was observed (pressure values between 20.6 and 192.9 mm Hg). The results indicate the use of modern soft-care systems depending on the individual risk of pressure sores.

The factors affecting distribution of anesthetic within the spinal column are of current interest due to recent reports of neurological injury occurring during spinal anesthesia. This paper describes a numerical model for simulating anesthetic dispersion, and applies the model to the evaluation of spinal-column size, anesthetic injection rate, and catheter orientation as factors influencing the anesthetic distribution. The model is based upon the finite-element method and incorporates a three-dimensional geometry derived from images of human spinal columns. Simulation results show that the ratio of the cross-sectional dimension of the subarachnoid space within the spinal column to the diameter of the catheter is a critical parameter, with low values of this ratio producing the most uniform anesthetic distributions. Increasing injection rate is found to produce a less uniform distribution in a global sense (higher total volume of anesthetic in the 'sacral' half) but a more uniform distribution in a localized sense (lower concentrations at critical points). Finally, the anesthetic distribution is demonstrated to be highly sensitive to orientation angle at high injection rates.

The importance of recognizing asymmetric Ga-67 citrate uptake in the sacroiliac region after bone marrow harvest and transplant is discussed in a case of non-Hodgkin's lymphoma. The patient underwent chemotherapy, irradiation, and autologous bone marrow transplant for stage IV disease. Ga-67 scintigraphy revealed sacroiliac asymmetry suggesting medial iliac reparative changes after bone marrow harvest. Iliac bone marrow biopsy showed no evidence of infection or of recurrent tumor. Subsequent follow-up imaging and open biopsy demonstrated lymphomatous invasion of adjacent soft tissue where initial findings were thought to represent benign, postharvest changes.

We describe on a primary, subcutaneous sacrococcygeal ependymoma presenting in a young female patient. Detailed immunohistochemical and electron microscopic examinations were performed. Out of the 40 similar cases reported in literature this is the first in which the determination of DNA content was also used to predict biological behaviour. The tumour proved to be aneuploid with low proliferative capacity in spite of absent histological signs of malignancy. It is suggested that DNA determination may be helpful in establishing prognosis and that it may contribute to a better understanding of the biological behaviour of this tumour.

Ten and 18-month-old female B6D2F1 mice were given promethazine HCl in their drinking water (2.0-4.0 mg/dl and 1.0 mg/dl, respectively) and age, sex and weight matched controls were given acidified tap water. The surviving mice were killed when they were 30.5 months old and femur, ilium and sacrum ash weights were determined. It was found that promethazine HCl effectively prevented age-related mineral loss at the higher does level. There was no evidence of excess morbidity or mortality among the mice given promethazine.