The addition of dydrogesterone improves the outcomes of pregnant women with low progesterone levels when receiving vaginal progesterone alone as luteal support in HRT-FET cycles.

Purpose: Vaginal progesterone (VP) alone has been used as luteal support (LS) in HRT-FET cycles without measuring serum progesterone concentrations (SPC) because it can achieve adequate intrauterine progesterone levels. However, several reports showed that the co-administration of progestin produced better outcomes than VP alone. We tried to address this discrepancy, focusing on SPC. Methods: VP was given to 180 women undergoing HRT-FET. We measured SPC when pregnancy was diagnosed on day 14 of LS. We compared assisted reproductive technology outcomes between VP alone versus VP + dydrogesterone (D). Results: When using VP alone, average SPC in the miscarriage cases (9.6 ng/mL) were significantly lower compared with the ongoing pregnancy (OP) cases (14.7 ng/mL). The cut-off value for progesterone, 10.7 ng/mL, was a good predictor for the subsequent course of the pregnancy. Of 76 women receiving D ± VP from the start of LS and achieving a pregnancy, the numbers of OP were 44 (84.6%) in SPC ≥ 10.7 ng/mL and 20 (83.3%) in SPC ≤ 10.7 ng/mL with no significant difference. Conclusion: VP alone resulted in lower SPC in some pregnant women in HRT-FET cycles and exhibited a lower OP rate. The co-administration of D improved an OP rate of low progesterone cases to the level comparable with non-low progesterone cases.

Evaluation of the Nature and Etiologies of Risk Factors for Diaphyseal Atypical Femoral Fractures.

OBJECTIVES: Differences in mechanisms of subtrochanteric and diaphyseal atypical femoral fractures (AFFs) are speculated in studies that analyzed differences in the patients' background. However, the etiologies of each type of AFF have not been studied in detail. This study aimed to investigate the nature and etiologies of the risk factors for diaphyseal AFFs. MATERIALS AND METHODS: Eighty consecutive Japanese patients with 91 diaphyseal AFFs (AFF group) and 110 age-matched women with osteoporosis (non-AFF control group) were included. Their clinical data were compared; factors affecting AFFs were investigated, and the etiologies of the risk factors for diaphyseal AFFs were examined. RESULTS: Multivariate analysis revealed that femoral serrated changes, bisphosphonate or denosumab usage, and lateral and anterior femoral curvatures were risk factors for diaphyseal AFFs (p < 0.0011, p = 0.0137, and p < 0.0001, respectively). Multivariate analyses revealed that serrated changes and low serum 25(OH)D levels affected the lateral curvature (p = 0.0088 and 0.0205, respectively), while serrated changes affected the anterior curvature (p = 0.0006), each significantly affected the femoral curvature. High serum calcium (Ca) levels, lateral femoral curvature, and anterior femoral curvature were predictors of serrated changes (p = 0.0146, 0.0002, and 0.0098, respectively). CONCLUSION: Risk factors for diaphyseal AFFs were bone resorption inhibitor usage, a strong femoral curvature, and serrated changes. Low serum 25(OH)D levels and serrated changes are risk factors for lateral curvature, while a high serum Ca level is a risk factor for serrated changes.

Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer.

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

Immunotherapy for Uterine Cervical Cancer Using Checkpoint Inhibitors: Future Directions.

Immune checkpoint inhibitors (ICIs) have demonstrated marked clinical effects worldwide, and "cancer immunotherapy" has been recognized as a feasible option for cancer treatment. Significant treatment responses have already been attained for malignant melanoma and lung cancer, ahead of gynecologic cancer. In cervical cancer, however, results are only available from phase II trials, not from phase III trials. Cervical cancer is a malignant tumor and is the fourth most common cancer among women worldwide. Since the introduction of angiogenesis inhibitors, treatment for recurrent and advanced cervical cancers has improved in the past five years, but median overall survival is 16.8 months for advanced cervical cancer, and all-stage five-year overall survival rate is 68%, indicating that treatment effects remain inadequate. For this reason, the development of new therapeutic approaches is imperative. We describe herein the KEYNOTE-158 and CheckMate 358 clinical trials, which were conducted for cervical cancer, and discuss future directions, including potential combinations with concurrent chemoradiation therapy (CCRT), as noted for other types of cancer.

Immunohistochemical analysis of the epithelial to mesenchymal transition in uterine carcinosarcoma.

OBJECTIVE: Uterine carcinosarcoma (UCS) is a highly aggressive neoplasm that is composed of an intricate admixture of carcinomatous and sarcomatous elements. The relationship between UCS and the epithelial to mesenchymal transition (EMT) has been reported. In this study, we examined how expression of E-cadherin was associated with the expression of EMT-related proteins in UCS. METHODS: UCS samples were histologically divided into three components: carcinomatous, transitional, and sarcomatous regions. Next, we examined the expression of E-cadherin and EMT-related proteins, including SNAI2, ZEB1, and TWIST1, in each component of the UCS using immunohistochemistry. The expression score was determined by combining the staining intensity and staining area of the target cells. RESULTS: The expression score of E-cadherin was significantly lower in transitional and sarcomatous components than in the carcinomatous component. In addition, a significant difference in the low expression score of E-cadherin between transitional and sarcomatous components (transitional > sarcomatous components) was found. There were significant differences between the expression scores of ZEB1 in the three components (sarcomatous > transitional > carcinomatous components). However, no difference in the expression of TWIST1 between the components was found. Conversely, the expression level of SNAI2 was higher in sarcomatous or transitional components than in the carcinomatous component. However, a significant difference between the transitional and sarcomatous components was not detected. CONCLUSION: These results suggest that the EMT plays an essential role in the pathogenesis of UCS.

Effects of eldecalcitol on bone and skeletal muscles in glucocorticoid-treated rats.

Glucocorticoids cause secondary osteoporosis and myopathy, characterized by type II muscle fiber atrophy. We examined whether a new vitamin D3 analogue, eldecalcitol, could inhibit glucocorticoid-induced osteopenia or myopathy in rats, and also determined the effects of prednisolone (PSL) and/or eldecalcitol on muscle-related gene expression. Six-month-old female Wistar rats were randomized into four groups: PSL group (10 mg/kg PSL); E group (0.05 µg/kg eldecalcitol); PSL + E group; and control group. PSL, eldecalcitol, and vehicles were administered daily for 2 or 4 weeks. Right calf muscle strength, muscle fatigue, cross-sectional areas (CSAs) of left tibialis anterior muscle fibers, and bone mineral density (BMD) were measured following administration. Pax7, MyoD, and myogenin mRNA levels in gastrocnemius muscles were also determined. Muscle strength was significantly higher in the PSL + E group than in the PSL group (p < 0.05) after 4 weeks, but not after 2 weeks. No significant difference in muscle fatigue was seen between groups at 2 or 4 weeks. CSAs of type II muscle fibers were significantly larger in the E group and the PSL + E group than in the PSL group at 4 weeks (p = 0.0093, p = 0.0443, respectively). Eldecalcitol treatment for 4 weeks maintained the same BMD as the PSL + E group. After 2 weeks, but not 4 weeks, eldecalcitol treatment significantly increased Pax7 and myogenin mRNA expression in gastrocnemius muscle, and PSL also stimulated myogenin expression. Eldecalcitol appears to increase muscle volume and to protect against femur BMD loss in PSL-administered rats, and it may also stimulate myoblast differentiation into early myotubes.

In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction.

Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for the development of Ras inhibitors, partly owing to the absence of well-defined surface pockets suitable for drug binding. Only recently, such pockets have been found in the crystal structures of a unique conformation of Ras⋅GTP. Here we report the successful development of small-molecule Ras inhibitors by an in silico screen targeting a pocket found in the crystal structure of M-Ras⋅GTP carrying an H-Ras-type substitution P40D. The selected compound Kobe0065 and its analog Kobe2602 exhibit inhibitory activity toward H-Ras⋅GTP-c-Raf-1 binding both in vivo and in vitro. They effectively inhibit both anchorage-dependent and -independent growth and induce apoptosis of H-ras(G12V)-transformed NIH 3T3 cells, which is accompanied by down-regulation of downstream molecules such as MEK/ERK, Akt, and RalA as well as an upstream molecule, Son of sevenless. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras(G12V) gene by oral administration. The NMR structure of a complex of the compound with H-Ras⋅GTP(T35S), exclusively adopting the unique conformation, confirms its insertion into one of the surface pockets and provides a molecular basis for binding inhibition toward multiple Ras⋅GTP-interacting molecules. This study proves the effectiveness of our strategy for structure-based drug design to target Ras⋅GTP, and the resulting Kobe0065-family compounds may serve as a scaffold for the development of Ras inhibitors with higher potency and specificity.

Preventing Loss of Femoral Periprosthetic Bone Mineral Density in Cementless Total Hip Arthroplasty Using a Tapered Wedge Stem: A Retrospective, Cohort Study in Osteoporotic Patients Treated with Denosumab.

Purpose: Bone quality is an important issue in elderly osteoporotic patients who undergo total hip arthroplasty (THA) because periprosthetic fracture or aseptic loosening of implant caused by periprosthetic bone loss is a serious concern. Denosumab has been approved for osteoporosis patients. Thus, the purpose of this study was to investigate whether denosumab prevents loss of proximal femoral periprosthetic bone mineral density (BMD) in cementless THA using a tapered wedge stem in patients with osteoporosis. Methods: Seventy consecutive patients who had undergone primary THA were included in this study. Twenty-seven patients who received denosumab for osteoporosis formed the denosumab group, and 43 patients without denosumab formed the control group. Bone turnover markers and femoral periprosthetic BMD were measured at two weeks, six months, and 12 months after THA. BMD was evaluated in seven regions of interest according to the zones of Gruen. Results: BMD in zone 1 was significantly increased from baseline at both six and 12 months after THA in the denosumab group (10.0±10.2%, p<0.001 and 13.1±12.7%, p<0.001, respectively) and significantly decreased in the control group (-3.6±9.7%, p<0.05, and -5.9±9.4%, p<0.001, respectively). BMD in zone 7 was significantly decreased compared to baseline at both six and 12 months after THA in the control group (-19.2±20.2%, p<0.001 and -22.3±16.8%, p<0.001, respectively) but not in the denosumab group (-0.7±18.5% and -1.1±16.6%, respectively). The use of denosumab for THA patients with osteoporosis was independently related to preventing loss of periprosthetic BMD of the femur at 12 months after surgery in zones 1 (p<0.001) and 7 (p<0.001) on multivariate analysis. Conclusions: Denosumab significantly increased proximal femoral periprosthetic BMD in zone 1 and prevented loss of BMD in zone 7 in patients with osteoporosis after cementless THA using a tapered wedge stem at both seven and 12 months. Future studies of denosumab treatment following THA in patients with osteoporosis should focus on clinical outcomes such as the risk of periprosthetic fracture and revision THA.

Diversity of neural-hemodynamic relationships associated with differences in cortical processing during bilateral somatosensory activation in rats.

The neural-hemodynamic relationships may vary depending on cortical processing patterns. To investigate how cortical hemodynamics reflects neural activity involving different cortical processing patterns, we delivered electrical stimulation pulses to rat hindpaws, unilaterally or bilaterally, and simultaneously measured electrophysiological (local field potential, LFP < 100 Hz; multiunit activity, MUA>300 Hz) and optical intrinsic signals associated with changes in cerebral blood volume (CBV). Unilateral stimulation evoked neural and optical signals in bilateral primary somatosensory cortices. Ipsilateral optical responses indicating an increased CBV exhibited a peak magnitude of ~30% and mediocaudal shifts relative to contralateral responses. Correlation analyses revealed different scale factors between contralateral and ipsilateral responses in LFP-MUA and LFP-CBV relationships. Bilateral stimulation at varying time intervals evoked hemodynamic responses that were strongly suppressed at 40-ms intervals. This suppression quantitatively reflected suppressed LFP responses to contralateral testing stimulation and not linear summation, with slowly fluctuating LFP responses to ipsilateral conditioning stimulation. Consequently, in the overall responses to bilateral stimulation, CBV-related responses were more linearly correlated with MUA than with LFPs. When extracting high-frequency components (>30 Hz) from LFPs, we found similar scale factors between contralateral and ipsilateral responses in LFP-MUA and LFP-CBV relationships, resulting in significant linear relationships among these components, MUA, and cortical hemodynamics in overall responses to bilateral stimulation. The dependence of LFP-MUA-hemodynamic relationships on cortical processing patterns and the LFP temporal/spectral structure is important for interpreting hemodynamic signals in complex functional paradigms driving diverse cortical processing.

Evaluation of factors affecting the occurrence of second atypical fracture after bone union of the first atypical fracture.

PURPOSE: Teriparatide is sometimes used in the treatment of atypical femoral fracture (AFF). Even if bone union is achieved, orthopedic physicians must consider the risk of relapse. This study aimed to investigate the factors affecting AFF recurrence, and to determine the appropriate treatment for osteoporosis after bone union. METHODS: One hundred thirty-one consecutive AFFs in 113 Japanese patients were included. Eleven patients had AFF in the unaffected limb (9 patients) after the first AFF or re-fracture at the original fracture site (2 patients) after bone union of the first AFF was confirmed. We divided all patients into two groups: the second fracture group (22 AFFs in 11 patients) and non-second fracture group (109 AFFs in 102 patients). We compared clinical information between the 2 groups and investigated the factors affecting AFF recurrence using the Student t-, Welch t-, and chi-square tests. RESULTS: Although there was no significant difference in clinical characteristics between the 2 groups, multivariate analysis of factors associated with AFF recurrence identified short duration of treatment with teriparatide and active vitamin D3 (p = 0.0408 and 0.0366, respectively) as risk factors. Even in the analysis excluding subtrochanteric AFF, short periods of teriparatide and active vitamin D3 administration were observed as risk factors (p = 0.0484 and 0.0346, respectively). CONCLUSION: The administration of teriparatide for as long as possible after occurrence first AFF and the use of active vitamin D3 after completion of teriparatide therapy may be the most effective strategy to prevent the recurrence of AFF.

Genome-wide analysis of microRNA to evaluate prognostic markers in isolated cancer glands and surrounding stroma in high-grade serous ovarian carcinoma.

The molecular mechanisms responsible for the progression of ovarian cancer remain incompletely understood. By targeting multiple cancer-related genes, microRNAs (miRNAs) have been identified as key regulators of cancer development and progression. In addition, the microenvironment, which constitutes cancer glands and the surrounding stromal tissue at the invasive front, has an important role in cancer progression. Using array-based analysis of 14 cases (cohort 1), the aim of the present study was to evaluate global miRNA expression in cancerous glands and surrounding stromal tissues (isolated using a crypt isolation method), in order to identify potential prognostic markers of high-grade serous carcinoma (HGSC). Reverse transcription-quantitative PCR was also used to verify the results in cohort 1 (14 cases) and in 16 additional HGSC cases (cohort 2; verification cohort). Firstly, miRNA expression levels were compared between HGSC and normal samples among both the isolated cancer gland and stromal tissue samples. Secondly, miRNA expression was compared between HGSC cases with recurrence and those without recurrence among the isolated cancer gland and stromal tissue samples. The results revealed six and seven miRNAs identified in both of the aforementioned comparisons in isolated cancer glands and surrounding stromal tissue, respectively. Furthermore, downregulation of miRNA-214-3p in isolated cancer glands and downregulation of miRNA-320c in the corresponding stromal tissue were associated with a decrease in disease-free survival (without recurrence) in cohort 2. These findings indicated that specific miRNAs expressed in cancer cells and surrounding stromal cells of HGSC may be potential biomarkers predicting patient prognosis.

Radiographic deformities of the lower extremity in patients with spontaneous osteonecrosis of the knee.

BACKGROUND: Spontaneous osteonecrosis of the knee (SONK) is one of the acute knee pain disorders arising in elderly patients. The presence of knee varus alignment and the size of necrotic area have been reported as the negative prognostic factors in prior studies. However, no previous study has yet clarified the radiological analysis of the lower extremity in SONK compared with that in osteoarthritis. The purpose of this study was therefore to identify the radiographic findings of the lower extremity in SONK. METHODS: Sixty-three knees of Kellgren-Lawrence classification grade 1 or 2 without any trauma treated between April 2012 and March 2014 were enrolled in this study. These knees were divided into two groups according to their magnetic resonance imaging (MRI) findings: SONK group (31 knees) and OA group (32 knees). Using a long leg standing X-ray, femorotibial angle (FTA), mechanical axis deviation (MAD), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA) and joint line convergent angle (JLCA) were compared between groups. Correlation between each parameter and the width ratio (WR) of the necrotic lesion were analyzed. RESULTS: FTA, MAD, MPTA and JLCA showed significant differences between the SONK and OA groups. In the SONK group, FTA was positively correlated with WR, and, MAD and MPTA was negatively correlated with WR. CONCLUSIONS: Compared with OA, SONK is associated with a significantly larger varus deformity at the proximal tibia, and larger joint play in the coronal plane.

Mesenteric extraovarian Sertoli-Leydig cell tumor without DICER1 hotspot mutation: a case report.

BACKGROUND: Ovarian Sertoli-Leydig cell tumors (SLCTs) with androgenic manifestations harbor DICER1 mutations in 30-60% of cases. Ovarian SLCTs without DICER1 hotspot mutations have been reported to exhibit elderly onset and no androgenic manifestations. We present the first case of a primary mesenteric SLCT without DICER1 hotspot mutation. CASE PRESENTATION: An 84-year-old woman presented with a 75-mm mesenteric solid tumor. She presented no androgenic or estrogenic manifestations. She underwent ileocecal resection. Histologically, her mesenteric tumor showed histopathological features that resembled moderately differentiated SLCT. Moreover, DICER1 hotspot mutation was not detected. CONCLUSIONS: We described the first case of heterotopic primary mesenteric SLCT without DICER1 hotspot mutation.

Effects of teriparatide on bone in autochthonous transgenic model mice for diabetes mellitus (Akita mice).

OBJECTIVES: The purpose of this study is to evaluate the effects of teriparatide (TPTD) on bone mineral density (BMD), bone strength, and bone quality in Akita mouse models of diabetes mellitus. METHODS: Twelve-week-old female Akita mice and control mice (C57/BL/6NCrSlc) were divided into 4 groups: control mice treated with vehicle (n = 7) or TPTD (n = 6); and Akita mice treated with vehicle (n = 6) or TPTD (n = 7). TPTD or vehicle was administered subcutaneously 3 times a week for 8 weeks. Blood glucose, serum sclerostin, total tibial BMD, femoral shaft bone strength, and bone quality using Fourier-transform infrared spectroscopy imaging were evaluated. RESULTS: No significant differences in serum sclerostin levels were evident among these groups after 8 weeks of treatment. TPTD significantly increased BMD in control mice (+12.7%, P = 0.02) and Akita mice (+29.2%, P = 0.001) compared with vehicle. Maximum load and stiffness were significantly higher in Akita mice treated with TPTD than in Akita mice treated with vehicle (+56.6%, P = 0.03 and + 90.5%, P = 0.02, respectively). On Fourier-transform infrared spectroscopy imaging, the mineral/matrix ratio was significantly lower in Akita mice treated with vehicle than in control mice (-12.2%, P = 0.02), and TPTD treatment significantly increased the mineral/matrix ratio (P = 0.003). CONCLUSIONS: TPTD thus improved BMD and bone strength in both control mice and Akita mice, with improvements in the mineral/matrix ratio among Akita mice.

Analgesic effects of minodronate in a rat chronic pain model.

We evaluated the analgesic effects of minodronate, alendronate and pregabalin on mechanical and thermal allodynia, as well as changes in bone mineral density and skeletal muscle volume caused by chronic constriction injury (CCI) in an ovariectomized rat. Ovariectomy was performed on four-week-old female Wistar rats. Thereafter, at 8-weeks of age, the left sciatic nerve was ligated to create the chronic pain model (CCI limb), and sham surgery was performed on the right hindlimb. In all rats, either minodronate (0.15 mg/kg/week), alendronate (0.15 mg/kg/week), pregabalin (10 mg/kg/week), or their vehicle was administered for 2 weeks starting on the 0th day of CCI. Behavioral evaluations, with von Frey testing and the hot plate test, were performed on days 0, 7 and 14. After 2 weeks, bilateral femurs and tibialis anterior muscles were harvested for bone mineral density and cross sectional area measurements, respectively. Two weeks treatment with minodronate significantly improved mechanical and thermal allodynia evaluated by the von Frey and hot plate tests in the CCI limb (P < 0.05). Minodronate and alendronate treatment for 2 weeks significantly increased total femoral bone mineral density in the CCI limb compared with pregabalin or vehicle treatment (P < 0.01). Cross sectional area of the CCI limb in the minodronate group was significantly larger than that of the alendronate group (P < 0.05) and pregabalin group (P < 0.05). Two-week treatment with minodronate, but not alendronate or pregabalin, improved mechanical and thermal allodynia caused by CCI in ovariectomized rats.

Neurite outgrowths of neurons with neurotrophin-coated carbon nanotubes.

Multiwalled carbon nanotubes (CNTs) coated with neurotrophin were used to regulate the differentiation and survival of neurons. Neurotrophin (nerve growth factor [NGF] or brain-derived neurotrophic factor [BDNF]) was covalently bound to CNTs modified by amino groups using a 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) reagent. The CNTs coated with NGF or BDNF promoted the neurite outgrowths of neurons in the same manner as soluble NGF and soluble BDNF. By enzyme-linked immunosorbent assay (ELISA), we demonstrated that neurotrophin-coated CNTs carry neurotrophin. These results suggest that neurotrophin-coated CNTs have biological activity and stimulate the neurite outgrowths of neurons.

Cut-Off Value of Medial Meniscal Extrusion for Knee Pain.

Purpose. Medial meniscal extrusion (MME) has attracted attention as an index of knee pain in conjunction with clinical symptoms that could be more useful than the diagnosis of knee osteoarthritis on X-ray. However, the size of MME that would cause knee pain has not been clarified. The aim of the present study was to investigate the cut-off value of MME for knee pain. Methods. A total of 318 knees were evaluated. The presence of current or past knee pain was confirmed by interview. Next, MME was measured using vertical sonographic images of the medial joint spaces during weightbearing. Results. Overall, 71 knees were painful (P-group), and 247 knees were not (N-group). MME was 5.9 ± 1.8 mm in the P-group and 2.9 ± 1.5 mm in the N-group (P < 0.0001). Analysis of the receiver operating characteristic curve showed that the cut-off value of MME for knee pain was 4.3 mm, with sensitivity of 0.8451 and specificity of 0.8502. In addition, 64% of knees without pain cases at the time of examination whose MME exceeded this cut-off value had past knee pain. Conclusions. The sensitivity and specificity of MME for knee pain were very high with a cut-off value of 4.3 mm.

Effects of combined therapy of alendronate and low-intensity pulsed ultrasound on metaphyseal bone repair after osteotomy in the proximal tibia of glucocorticoid-induced osteopenia rats.

OBJECTIVES: Glucocorticoid (GC) treatment inhibits activation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation from stem cells. As a result, GC treatment results in bone loss, GC-induced osteoporosis (GIO), elevated fracture risk, and delayed bone healing. Bisphosphonates such as alendronate (ALN) are recommended for treating or preventing GIO, and low-intensity pulsed ultrasound (LIPUS) facilitates fracture healing and maturation of regenerated bone. Combined therapy with ALN and LIPUS may stimulate cancellous bone healing in GIO rats. Here, we examined the effect of ALN and LIPUS on cancellous bone osteotomy repair in the proximal tibia of GIO rats. METHODS: Prednisolone (10 mg/kg body weight/day) was administered for 4 weeks to induce GIO in 6-month-old female Sprague-Dawley rats. Tibial osteotomy was then performed and daily subcutaneous injection of ALN (1-µg/kg body weight) was subsequently administered alone or in combination with LIPUS (20 min/day) for 2 or 4 weeks. RESULTS: ALN significantly increased bone mineral density (BMD) at 2 and 4 weeks, and ALN + LIPUS significantly increased BMD at 4 weeks. Bone union rates were significantly increased after 2 and 4 weeks ALN and ALN + LIPUS treatment. Lastly, ALN and ALN + LIPUS significantly increased the proportion of Runx2 positive cells at 4 weeks. CONCLUSIONS: ALN monotherapy and combined ALN and LUPUS treatment augmented BMD and stimulated cancellous bone repair with increased Runx2 expression at the osteotomy site in GIO rats. However, the combined treatment had no additional effect on cancellous bone healing compared to ALN monotherapy.

Resting hypofrontality in schizophrenia: A study using near-infrared time-resolved spectroscopy.

Hypofrontality has been a major finding obtained from functional neuroimaging studies on schizophrenia, although there have also been contradictory results that have questioned the reality of hypofrontality. In our previous study, we confirmed the existence of activation hypofrontality by using a 2-channel continuous-wave-type (CW-type) near-infrared spectroscopy (NIRS) instrument. In this study, we employed a single-channel time-resolved spectroscopy (TRS) instrument, which can quantify hemoglobin (Hb) concentrations based on the photon diffusion theory, to investigate resting hypofrontality. A pair of incident and detecting light guides was placed on either side of the forehead at approximately Fp2-F8 or Fp1-F7 alternately in 14 male schizophrenic patients and 16 age-matched male control subjects to measure Hb concentrations at rest. The patients were also measured with a 2-channel CW-type NIRS instrument during the performance of a random number generation (RNG) task. A reduced total hemoglobin concentration (t-Hb) less than 60 microM (the mean value of the control subjects-1.5 SD) was observed bilaterally in 4 patients and only in the left side in 3 patients. Activation hypofrontality was more manifest in these patients than in the remaining 7 patients despite the same task performance. This decreased t-Hb was related to the duration of illness, and it was not observed in patients whose duration of illness was less than 10 years. These results indicate that resting hypofrontality is a chronically developed feature of schizophrenia. This does not necessarily represent frontal dysfunction, but may reflect anatomical and/or functional changes in frontal microcirculation.

Extraction of depth-dependent signals from time-resolved reflectance in layered turbid media.

We try a new approach with near-IR time-resolved spectroscopy, to separate optical signals originated in the upper layer from those in the lower layer and to selectively determine the absorption coefficient (mu(a)) of each layer in a two-layered turbid medium. The difference curve in the temporal profiles of light attenuation between a target and a reference medium is divided into segments along the time axis, and a slope of each segment is calculated to determine the depth-dependent mu(a). The depth-dependent mu(a) values are estimated under various conditions in which mu(a) and the reduced scattering coefficient (mu(s)') of each layer are changed with a Monte Carlo simulation and in phantom experiments. Temporal variation of them represents the difference in mu(a) between two layers when mu(s)' of a reference is the same as that of the upper layer of the target. The discrepancies between calculated mu(a) and the real mu(a) depend on the ratio of the real mu(a) of the upper layer to that of the lower layer, and our approach enables us to estimate the ratio of mu(a) between the two layers. These results suggest the potential that mu(a) of the lower layer can be determined by our procedure.