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Background We developed a porous Ti alloy/PEEK composite interbody cage by utilizing the advantages of polyetheretherketone (PEEK) and titanium alloy (Ti alloy) in combination with additive manufacturing technology. Methods Porous Ti alloy/PEEK composite cages were manufactured using various controlled porosities. Anterior intervertebral lumbar fusion and posterior augmentation were performed at three vertebral levels on 20 female pigs. Each level was randomly implanted with one of the five cages that were tested: a commercialized pure PEEK cage, a Ti alloy/PEEK composite cage with nonporous Ti alloy endplates, and three composite cages with porosities of 40, 60, and 80%, respectively. Micro-computed tomography (CT), backscattered-electron SEM (BSE-SEM), and histological analyses were performed. Results Micro-CT and histological analyses revealed improved bone growth in high-porosity groups. Micro-CT and BSE-SEM demonstrated that structures with high porosities, especially 60 and 80%, facilitated more bone formation inside the implant but not outside the implant. Histological analysis also showed that bone formation was higher in Ti alloy groups than in the PEEK group. Conclusion The composite cage presents the biological advantages of Ti alloy porous endplates and the mechanical and radiographic advantages of the PEEK central core, which makes it suitable for use as a single implant for intervertebral fusion.

Long-term opioid therapy for chronic pain may lead to analgesic tolerance, especially when administered intrathecally, thus preventing adequate pain relief. Discovering drug targets to treat opioid tolerance using a mechanism-based approach targeting opioid-induced neuroinflammation provides new therapeutic opportunities. In this study, we provide translational evidence that CXCL12/CXCR4 signaling contributes to the pathogenesis of opioid tolerance.The CXCL12 levels in the cerebrospinal fluid of opioid-tolerant patients were compared with those of opioid-naive subjects. For further investigation, a rodent translational study was designed using 2 clinically relevant opioid delivery paradigms: daily intraperitoneal morphine injections and continuous intrathecal morphine infusion. We measured rats' tail flick responses and calculated the percentage of maximum possible effects (%MPE) to demonstrate opioid acute antinociception and the development of analgesic tolerance. The effects of exogenous CXCL12, CXCL12 neutralizing antibody, and receptor antagonist AMD3100 were investigated by intrathecal administration. Data were presented as mean ± SEM.CXCL12 was significantly upregulated in the cerebrospinal fluid of opioid-tolerant patients for 892 ± 34 pg/mL (n = 27) versus 755 ± 33 pg/mL (n = 10) in naive control subjects (P = .03). Furthermore, after 2 and 5 days of intrathecal morphine infusion, rat lumbar spinal cord dorsal horn CXCL12 messenger RNA levels were significantly upregulated by 3.2 ± 0.7 (P = .016) and 3.4 ± 0.3 (P = .003) fold, respectively. Results from the daily intraperitoneal morphine injection experiments revealed that administering an intrathecal infusion of CXCL12 for 24 hours before the first morphine injection did not decrease antinociception efficacy on day 1 but accelerated tolerance after day 2 (%MPE 49.5% vs 88.1%, P = .0003). In the intrathecal morphine coinfusion experiments, CXCL12 accelerated tolerance development (%MPE 9.4% vs 43.4% on day 1, P.0001), whereas coadministration with CXCL12 neutralizing antibody attenuated tolerance (72.5% vs 43.4% on day 1, P.0001; 47.6% vs 17.5% on day 2, P.0001). Coadministration of receptor antagonist AMD 3100 can persistently preserve morphine analgesic effects throughout the study period (27.9% ± 4.1% vs 0.9% ± 1.6% on day 5, P = .03).The CXCL12/CXCR4 pathway contributes to the pathogenesis of opioid tolerance. Our study indicates that intervening with CXCL12/CXCR4 signaling has therapeutic potential for opioid tolerance.

Objective: The aim of this retrospective observational study was to determine the efficacy of carbetocin in reducing blood loss and primary postpartum hemorrhage (PPH) in vaginal and cesarean deliveries in a tertiary hospital in Taiwan. Materials and methods: Eligible gravid women (27–41 weeks) with available data were categorized into those treated prophylactically with and without carbetocin. The primary outcome was blood loss and incidence of primary PPH as measured by intrapartum/intraoperative and postpartum (recovery room) blood loss. Results: A total of 1069 deliveries were evaluated. Maternal age (∼31 years of age), body mass index (∼27 kg/m2) and parity (∼1.4) were similar among those treated with and without carbetocin for both vaginal and cesarean deliveries. The majority [749/1069 (70.1%)] of deliveries were vaginal; a similar proportion of women undergoing vaginal [221/749 (29.5%)] and cesarean [110/320 (34.4%)] deliveries received prophylactic carbetocin for prevention of PPH. Among vaginal deliveries, there was no significant difference in intrapartum (p = 0.083) or postpartum (p = 0.925) blood loss, or incidence of PPH (p = 0.092) between women with versus without carbetocin prophylaxis. However, there was a significant reduction in the intraoperative and total blood loss among cesarean deliveries with versus without carbetocin prophylaxis (p

Objective: To examine the factors affecting pregnant women's decisions to accept or decline the prenatal pertussis (Tdap) vaccination in Taiwan. Materials and methods: We conducted a cross-sectional survey, recruiting pregnant women who had received prenatal care from eight maternity hospitals between January and December 2018. We examined the participants’ demographic characteristics, perceptions of pertussis disease risk and vaccination effectiveness, beliefs regarding vaccine information, physician recommendation, and other potential factors affecting decision-making regarding prenatal vaccination. Results: The complete survey response rate among eligible women was 78%. Among the participants, 74% accepted and 26% declined prenatal Tdap vaccination. Most women accepted Tdap during pregnancy because of perceived severity of pertussis in their infants, perceived effectiveness of the prenatal Tdap in preventing neonatal pertussis, and perceived safety of the prenatal Tdap vaccine for the fetus, as well as a provider's recommendation, which was the factor strongly associated with actual Tdap reception. Most of the participants who accepted Tdap vaccination during pregnancy and who believed that the Tdap vaccine could protect their infants from pertussis reported the receiving sufficient information to make an informed decision and trust in the information. By contrast, a large proportion of the participants who declined Tdap and who did not want to experience possible fetal side effects of Tdap reported not getting sufficient information to make an informed decision and a lack of trust in the information. Conclusion: Developing a comprehensive strategy involving government policy, the health care system, public media, health professionals, and pregnant women to launch a successful campaign may improve the nationwide acceptance of the prenatal pertussis vaccination. Keywords: Pertussis, Vaccine, Prenatal

As human beings live longer, age-related diseases such as osteoporosis will become more prevalent. Intolerant side effects and poor responses to current treatments are observed. Therefore, novel effective therapeutic agents are greatly needed. Here, pyrazole derivatives were designed and synthesized, and their osteoclastogenesis inhibitory effects both in vitro and in vivo were evaluated. The most promising compound 13 with a 2-(dimethylamino)ethyl group inhibited markedly in vitro osteoclastogenesis as well as the bone resorption activity of osteoclasts. Compound 13 affected osteoclast's early proliferation and differentiation more than later fusion and maturation stages. In ovariectomized (OVX) mice, compound 13 can inhibit the loss of trabecular bone volume, trabecular bone number, and trabecular thickness. Moreover, compound 13 can antagonize OVX-induced reduction of serum bone resorption marker and then compensatory increase of the bone formation marker. To sum up, compound 13 has high potential to be developed into a novel therapeutic agent for treating osteoporosis in the future.

ObjectiveWe describe a prenatal molecular diagnosis of hypochondroplasia (HCH) in a pregnancy not at risk of HCH and review the literature on prenatal diagnosis of HCH.Case reportA 28-year-old primigravid woman was referred for genetic counseling at 30 weeks of gestation because of short-limbed dwarfism in the fetus. The woman had a body height of 152 cm. Her husband had a body height of 180 cm. Level II ultrasound showed a normal amount of amniotic fluid and a singleton fetus with fetal biometry equivalent to 30 weeks except for short limbs. Fetal biometry measurements were as follows: biparietal diameter = 7.38 cm (30 weeks); head circumference = 28.14 cm (30 weeks); abdominal circumference (AC) = 24.64 cm (30 weeks); femur length (FL) = 3.97 cm ( 0.18); humerus = 3.64 cm ( G, TAC > TGC transversion in exon 7 leading to a p.Tyr278Cys (Y278C) mutation in the FGFR3 protein. aCGH analysis revealed no genomic imbalance in cord blood. After delivery, the fetus had short limbs, a narrow thorax, brachydactyly, and relative macrocephaly. Cytogenetic analysis of cultured placental cells revealed a karyotype of 46,XX.ConclusionPrenatal diagnosis of abnormal ultrasound findings suspicious of ACH should include a differential diagnosis of HCH by molecular analysis of FGFR3.

Dextromethorphan (DXM), a commonly used antitussive, is a dextrorotatory morphinan. Here, we report that DXM inhibits the receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption by abrogating the activation of NF-κB signalling in vitro. Oral administration of DXM ameliorates ovariectomy (OVX)-induced osteoporosis in vivo. DXM was reported to possess anti-inflammatory properties through inhibition of the release of pro-inflammatory factors. However, the potential role and action mechanism of DXM on osteoclasts and osteoblasts remain unclear. In this study, in vitro and in vivo studies were performed to investigate the potential effects of DXM on osteoclastogenesis and OVX-induced bone loss. Osteoclastogenesis was examined by the TRAP staining, pit resorption, TNF-α release, and CCR2 and CALCR gene expression. Osteoblast differentiation was analyzed by calcium deposition. Osteogenic and adipogenic genes were measured by real-time PCR. Signaling pathways were explored using Western blot. ICR mice were used in an OVX-induced osteoporosis model. Tibiae were measured by µCT and serum markers were examined with ELISA kits. DXM inhibited RANKL-induced osteoclastogenesis. DXM mainly inhibited osteoclastogenesis via abrogation of IKK-IκBα-NF-κB pathways. However, a higher dosage of DXM antagonized the differentiation of osteoblasts via the inhibition of osteogenic signals and increase of adipogenic signals. Oral administration of DXM (20 mg/kg/day) partially reduced trabecular bone loss in ovariectomized mice. DXM inhibits osteoclast differentiation and activity by affecting NF-κB signaling. Therefore, DXM at suitable doses may have new therapeutic applications for the treatment of diseases associated with excessive osteoclastic activity.

Oncostatin M (OSM) belongs to IL-6 subfamily and is mostly produced by T lymphocytes. High levels of OSM are detected in the pannus of rheumatoid arthritis (RA) patients and it may arouse the inflammation responses in joints and eventually leads to bone erosion. Placenta growth factor (PLGF) is an angiogenic factor and highly homologous with vascular endothelial growth factor (VEGF). It has been recently reported that PLGF is highly expressed in synovial tissue and enhances the production of proinflammatory cytokines including TNF-α and IL-6. Here, we demonstrated that OSM increased mRNA and protein levels of PLGF in a time- and concentration-dependent manner in RA synovial fibroblasts. Inhibitors of JAK3 and PI3K antagonized OSM-induced production of PLGF. OSM enhanced the phosphorylation of Tyr705-STAT3, Ser727-STAT3, Ser473-Akt, and increased the nuclear translocation of phosphorylated STAT3 time-dependently. Transfection of dominant negative Akt or application of PI3K inhibitorLY294002 significantly inhibited p-Tyr705-STAT3, p-Ser727-STAT3, and PLGF expression, indicating that Akt is involved in JAK3/STAT3/PLGF signaling cascade. To further examine whether STAT3 binds to the promoter region of PLGF, Chip assay was used and it was found that OSM could bind with PLGF promoter, which was inhibited by JAK3 and PI3K inhibitors. Accumulation of PLGF in the pannus may contribute to the inflammation, angiogenesis and joints destruction in RA patients. These findings demonstrated the important role of OSM in the pathology network of RA and provided novel therapeutic drug targets for RA treatment.

Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-matrix interaction. The vitronectin and osteopontin receptor αvβ3 integrin has increased expression levels and is implicated in the adhesion, activation, and migration of osteoclasts on the bone surface as well as osteoclast polarization. αvβ3 integrin plays an important role in osteoclast differentiation and resorption. In addition, Arg-Gly-Asp (RGD)-containing peptides, small molecular inhibitors, and antibodies to αvβ3 integrin have been shown to inhibit bone resorption in vitro and in vivo. Here we examined the effects of a disintegrin HSA-ARLDDL a genetically modified mutant of rhodostomin conjugated with human serum albumin, which is highly selective of αvβ3, on RANKL-induced osteoclastogenesis and ovariectomy (OVX)-induced osteoporosis. In RANKL-induced osteoclastogenesis, HSA-ARLDDL significantly inhibited osteoclast formation, and IC50 was at nM range. Post-treatment HSA-ARLDDL also inhibits osteoclast formation. Furthermore, weekly administration of HSA-ARLDDL significantly inhibits the increase in serum bone resorption marker levels and decrease in cancellous bone loss in tibia and femur induced by OVX. On the other hand, HSA-ARLDDL did not affect the differentiation and calcium deposition of osteoblasts. These results indicate that the highly selective and long-acting αvβ3 integrin antagonists could be developed as effective drugs for postmenopausal osteoporosis.

Background This study evaluated the incidence, nature, and seriousness of adverse drug reactions (ADRs) occurring after AdimFlu-S® influenza A (H1N1) vaccination in pregnant women was administered. Methods This is a retrospective cohort study. Between October 2009 and February 2010, 198 pregnant women who had received the AdimFlu-S® influenza A (H1N1) vaccine during pregnancy and 198 age-matched pregnant women who had not received influenza vaccine were included and recorded. The pregnancy outcome and maternal adverse effects were extracted from chart reviews. Infant health status data were followed up until 8 weeks post-partum. Results During the observation period of each cohort, four subjects (2.0%) in the exposed group experienced vaccine-related adverse events that were mild in severity. A total of 17 women (8.6%) in the vaccine exposed group and 40 women (20.2%) in the unexposed group underwent at least one adverse effect during their pregnancy. A total of 72 infants (35.6%) in the exposed group and 101 infants (49%) in the unexposed group had at least one adverse event within 8 weeks after they were born (p

Objective(s) Pregnancy is rare in patients on chronic dialysis, with only a 30–50% rate of successful delivery reported in a previous review article. The pregnancy outcome has improved in recent decades, but data on pregnancy outcome are limited due to the small sample size of previous case series. This study investigated the pregnancy outcome in patients on chronic dialysis over the past 15 years in a single center, and also performed a combined analysis of results of individual cases from previously reported series to obtain overall estimates of rates of successful delivery. Study design Medical records for a total of 13 pregnancies in 13 women undergoing chronic dialysis (10 on hemodialysis and 3 on peritoneal dialysis) during the period from 1990 to 2006 in our hospital were retrospectively reviewed. Data on the changes in dialysis regimen, medical complications, obstetric conditions, and perinatal problems were collected. An electronic search of PubMed identified 10 case series studies and 12 case reports published after 1990 with adequate individual information available. Pooled data from a total of 131 cases, including our patients (117 hemodialysis and 14 peritoneal dialysis), were analyzed using the χ 2 -test and the t -test to compare the rate of successful delivery and birth weight in the hemodialysis group and the peritoneal dialysis group, and in pregnancies with conception prior to and those with conception after starting dialysis. Results Among the 10 pregnant women who decided to continue their pregnancies in our hospital, 5 delivered live newborns and 5 pregnancies ended with intra-uterine fetal demise or neonatal death. The overall rate of successful delivery was 70.9% (83 out of 117) in patients on hemodialysis and 64.2% (9/14) in patients on peritoneal dialysis. The birth weight for these groups was 1483 ± 116 and 1623 ± 320 g, respectively. The difference in the rates of successful delivery in these two groups was not significant ( p = 0.61). However, the birth weight was significantly greater in patients who conceived after than those who conceived prior to starting hemodialysis (1529 ± 132 g versus 1245 ± 200 g; p = 0.04). Conclusions This study found that the outcome of pregnancy on chronic dialysis has improved in recent decades, but our study showed no significant difference in the rate of successful delivery between patients on hemodialysis and those on peritoneal dialysis.

The pivotal role of glial activation and up-regulated inflammatory mediators in the opioid tolerance has been confirmed in rodents but not yet in humans. Here, the authors investigated the intraspinal cytokine and chemokine profiles of opioid-tolerant cancer patients; and to determine if up-regulated chemokines could modify opioid tolerance in rats.Cerebrospinal fluid samples from opioid-tolerant cancer patients and opioid-naive subjects were compared. The cerebrospinal fluid levels of tumor necrosis factor-alpha, CXCL1, CXCL10, CCL2, and CX3CL1 were assayed. The rat tail flick test was utilized to assess the effects of intrathecal CXCL1 on morphine-induced acute antinociception and analgesic tolerance.CXCL1 level in cerebrospinal fluid was significantly up-regulated in the opioid-tolerant group (n = 30, 18.8 pg/ml vs. 13.2 pg/ml, P = 0.02) and was positively correlated (r = 0.49, P0.01) with opioid dosage. In rat experiment, after induction of tolerance by morphine infusion, the spinal cord CXCL1 messenger RNA was up-regulated to 32.5 ± 11.9-fold. Although CXCL1 infusion alone did not affect baseline tail-flick latency, the analgesic efficacy of a single intraperitoneal injection of morphine dropped significantly on day 1 to day 3 after intrathecal infusion of CXCL1. After establishing tolerance by intrathecal continuous infusion of morphine, its development was accelerated by coadministration of CXCL1 and attenuated by coadministration of CXCL1-neutralizing antibody or CXCR2 antagonist.CXCL1 is up-regulated in both opioid-tolerant patients and rodents. The onset and extent of opioid tolerance was affected by antagonizing intrathecal CXCL1/CXCR2 signaling. Therefore, the CXCL1/CXCR2 signal pathway may be a novel target for the treatment of opioid tolerance.

Objective To present a rare case of fetal nonfamilial proximal femoral focal deficiency (PFFD) diagnosed as early as 21 weeks' gestation. Case Report A 32-year-old woman was referred to our hospital at 21 weeks' gestation. An ultrasound examination revealed isolated unilateral short femur (right femur = 27.3 mm and left femur = 37.9 mm). The measurements of all the remaining long bones were within the normal range. The facial profile was unremarkable. Results of amniocentesis revealed a normal 46,XX female karyotype. A follow-up ultrasound 2 weeks later demonstrated further discrepancy in femoral length. A diagnosis of PFFD was made. The parents were well informed about the treatment options and after counseling they decided to terminate the pregnancy. A postmortem X-ray examination confirmed the diagnosis of PFFD. Conclusion We have to measure both sides of extremities according to the ultrasound scan guidelines so as not to overlook any possible case of skeletal dysplasia. An advanced three-dimensional (3D) and 4D ultrasound evaluation of the bony structures and carefully observing the range of mention of the affect limbs will provide proper information to formulate a further therapeutic plan.

Sheng-Kai Wu,1 Chi-Feng Chiang,1 Yu-Hone Hsu,1,4 Tzu-Hung Lin,2 Houng-Chi Liou,2 Wen-Mei Fu,2 Win-Li Lin1,3 1Institute of Biomedical Engineering, College of Medicine and College of Engineering, 2Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan; 4Department of Neurosurgery, Cheng-Hsin General Hospital, Taipei, Taiwan Abstract: The blood–brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers. Keywords: hyperthermia, focused ultrasound (FUS), pegylated liposomal doxorubicin (PLD), brain metastasis of breast cancer

Objective To present intensive intrauterine treatment of recurrent early onset fetal erythroblastosis due to anti-M alloimmunization. Case Report A 33-year-old woman, gravid 3, para 1, had anti-M IgG antibody, which caused alloimmunization of her previous pregnancies. This time she visited our hospital for intensive intervention. No evidence of fetal hydrops was found during ultrasound examination at 12 weeks of gestation. Plasmapheresis was given from 17 weeks of gestation but fetal erythroblastosis still developed 1 week later. Two intraperitoneal transfusions and one intracardiac transfusion were given within three days but fetal erythroblastosis still progressed to fetal bradycardia and occasional asystole. Epinephrine resuscitation could only temporarily improve the fetal heart rate and fetal death was inevitable. Conclusion Serial measurements of fetal middle cerebral artery peak systolic velocities, advanced plasmapheresis, intrauterine blood transfusion, and, if needed, intravenous immunoglobulin supplement, may be the appropriate treatment for early onset fetal erythroblastosis resulting from alloimmunization.

Objective Fetal intracranial hemorrhage (ICH) in utero is a rare complication of pregnancy associated with subsequent neurological sequelae or fetal death. Case report A 34-year-old woman with Crohn's disease presented at 36 weeks' gestation due to decreased fetal movement. Fetal heart-rate tracing indicated poor beat-to-beat variability. In addition, a Doppler ultrasonography suggested a prenatal stroke with evidences of ICH, reverse-end diastolic velocity of the middle cerebral artery, and a persistent distended bladder. A nonaggressive treatment option was chosen after counseling about the unfavorable prognosis. However, 22 hours after her admission, intrauterine fetal death occurred. Conclusion Fetal ICH in utero might be a rare yet lethal complication of Crohn's disease in pregnancy.

Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan Department of Biotechnology, Asia University, Taichung, Taiwan d School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan e Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan Department of Obstetrics and Gynecology, School of Medicine, Taipei Medical University, Taipei, Taiwan Dianthus Maternal Fetal Medicine Clinic, Taipei, Taiwan Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Bioengineering, Tatung University, Taipei, Taiwan