Although bone marrow (BM) or mobilized peripheral blood (PB) is frequently used as the source of hematopoietic stem cells, hematopoietic stem cell transplantation (HSCT) using cord blood (CB) is gradually gaining popularity in many countries. However, BM or PB is still preferred over CB in Korea. Therefore, we tried to assess the awareness of CB transplantation (CBT) among domestic HSCT physicians and develop strategies for boosting its utilization by administering questionnaires to some of these physicians.
A direct questionnaire survey was conducted using the "Audience Response System" among 301 members who attended the annual meeting of the Korean Society of Blood and Marrow Transplantation. The data were analyzed for only 67 board certified physicians who were directly involved in HSCT activities.
The poor outcomes resulting from insufficient experience in CBT was designated by the physicians as the main reason for the low domestic implementation of HSCT using CB. Other reasons identified in the survey were distrust in the quality and management of domestic CB and the high cost of obtaining CB.
Increasing the use of donated CB would foremost require increasing the inventory of donated CB containing a sufficient cell number for CBT and securing structured quality control of the CB banks. In addition, it would be necessary to minimize CB supply costs and continue to provide academic data, including CBT guidelines, so that clinicians could perform CBT with more confidence.
Cord blood; Utilization; Questionnaire
GC7101, an extract of Lonicera Flos, is a novel developing drug for reflux esophagitis and functional dyspepsia. However, the drug’s exact pharmacological mechanism of action remains unclear. This study assessed the effects of GC7101 on gastrointestinal (GI) motor function.
We used male guinea pigs to evaluate the effects of GC7101 on GI motility. The contraction of antral circular muscle in the presence of different doses of GC7101 was measured in a tissue bath. The prokinetic effects of GC7101 were tested using the charcoal transit assay from the pylorus to the most distal point of migration of charcoal mixture. To clarify the mechanism of action of GC7101, atropine, dopamine and the selective 5-hydroxytryptamine 4 receptor antagonist, GR113808 were used.
The maximal amplitude of circular muscle contraction was induced by 5 mg mL−1 GC7101. The area under the curve of contraction was significantly increased at 5 mg mL−1 GC7101. Addition of 10−6 M atropine, 10−8 M dopamine or 10−7 M GR 113808 to GC7101 5 mg mL−1 decreased the amplitude and area under curve compared to GC7101 5 mg mL−1 alone. GC7101 accelerated GI transit in a dose dependent manner except 100 mg kg−1. Delayed GI transit caused by atropine, dopamine and GR 113808 was restored by GC7101 50 mg kg−1.
GC7101, an extract of Lonicera Flos, exerts a gastric prokinetic effect in guinea pig through cholinergic, antidopaminergic and serotonergic mechanisms. Therefore, GC7101 might be a novel drug for the treatment of functional dyspepsia.
Functional dyspepsia; Gastrointestinal motility; Lonicera Flos; Prokinetic
The aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA).
A systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches.
Five RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies.
Tofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile.
Tofacitinib; Efficacy; Safety; Arthritis, rheumatoid
Cord blood (CB) has been used as an important and ethical source for hematopoietic stem cell transplantation (SCT) as well as cell therapy by manufacturing mesenchymal stem cell, induced pleuripotential stem cell or just isolating mononuclear cell from CB. Recently, the application of cell-based therapy using CB has expanded its clinical utility, particularly, by using autologous CB in children with refractory diseases. For these purposes, CB has been stored worldwide since mid-1990. In this review, I would like to briefly present the historical development of clinical uses of CB in the fields of SCT and cell therapy, particularly to review the experiences in Korea. Furthermore, I would touch the recent banking status of CB.
Cord blood; Transplantation; Cell therapy
Our aim was to investigate the clinical pattern of hemophagocytic lymphohistiocytosis following Kawasaki disease (HLH-KD), to enable differentiation of HLH from recurrent or refractory KD and facilitate early diagnosis.
We performed a nationwide retrospective survey and reviewed the clinical characteristics of patients with HLH-KD, including the interval between KD and HLH, clinical and laboratory findings, treatment responses, and outcomes, and compared them with historical data for both diseases.
Twelve patients with HLH-KD, including 5 previously reported cases, were recruited. The median age was 6.5 years (range, 9 months-14.7 years). Eight patients were male and 4 were female. The median interval between the first episode of KD and the second visit with recurrent fever was 12 days (3-22 days). Of the 12 children, 2 were initially treated with intravenous IgG (IVIG) for recurrent KD when they presented at the hospital with recurrent fever. Eventually, 10 children received chemotherapy under an HLH protocol and 2 received supportive treatment. Two patients died of combined infections during chemotherapy, 1 was lost to follow up, and 9 remain alive. The overall survival rate at 4 years was 81.1% with a median follow up of 45.1 months.
A diagnosis of HLH-KD should be considered when symptoms similar to recurrent KD develop within 1 month of the first episode of KD. Our findings will help physicians differentiate between HLH and the recurrent form of KD.
Hemophagocytic lymphohistiocytosis; Kawasaki disease; Recurrent
We assessed the efficacy and safety of bosentan in patients with pulmonary arterial hypertension (PAH).
We surveyed randomized controlled trials (RCTs) of the efficacy and safety of bosentan in patients with PAH using MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and manual searches. Meta-analysis of RCTs was performed to determine treatment efficacy and safety outcomes. Results are presented as odds ratios (ORs) or weighted mean differences (WMDs).
Meta-analysis of seven RCTs including a total of 410 patients and 296 controls revealed that the 6-minute work distance was significantly higher in the bosentan group than in the placebo group (WMD, 46.19; 95% confidence interval [CI], 21.20 to 71.19; p = 2.9 × 10-5). Compared with the placebo, bosentan significantly reduced the mean pulmonary arterial pressure in patients with PAH (WMD, -6.026; 95% CI, -8.785 to -3.268, p = 1.8 × 10-6). The bosentan therapy group worsened less clinically than the placebo group (OR, 0.252; 95% CI, 0.140 to 0.454; p = 4.6 × 10-7). The incidence of serious adverse events did not differ between the bosentan and placebo groups (OR, 0.948; 95% CI, 0.556 to 1.614; p = 0.843). However, the results of the abnormal liver function test (LFT) were significantly higher in the bosentan group than in the placebo group (OR, 2.312; 95% CI, 1.020 to 5.241; p = 0.045).
This meta-analysis shows that bosentan can treat PAH effectively. However, bosentan increased the incidence of abnormal LFT results compared with the placebo.
Bosentan; Efficacy; Safety; Hypertension, pulmonary
We evaluated the effect of human parathyroid hormone (hPTH) on the engraftment and/or in vivo expansion of hematopoietic stem cells in an umbilical cord blood (UCB)-xenotransplantation model. In addition, we assessed its effect on the expression of cell adhesion molecules.
Materials and Methods
Female NOD/SCID mice received sublethal total body irradiation with a single dose of 250 cGy. Eighteen to 24 hours after irradiation, 1×107 human UCB-derived mononuclear cells (MNCs) and 5×106 human UCB-derived mesenchymal stem cells (MSCs) were infused via the tail vein. Mice were randomly divided into three groups: Group 1 mice received MNCs only, Group 2 received MNCs only and were then treated with hPTH, Group 3 mice received MNCs and MSCs, and were treated with hPTH.
Engraftment was achieved in all the mice. Bone marrow cellularity was approximately 20% in Group 1, but 70-80% in the hPTH treated groups. Transplantation of MNCs together with MSCs had no additional effect on bone marrow cellularity. However, the proportion of human CD13 and CD33 myeloid progenitor cells was higher in Group 3, while the proportion of human CD34 did not differ significantly between the three groups. The proportion of CXCR4 cells in Group 3 was larger than in Groups 1 and 2 but without statistical significance.
We have demonstrated a positive effect of hPTH on stem cell proliferation and a possible synergistic effect of MSCs and hPTH on the proportion of human hematopoietic progenitor cells, in a xenotransplantation model. Clinical trials of the use of hPTH after stem cell transplantation should be considered.
Umbilical cord blood; parathyroid hormone; bone marrow niches
We describe 2 cases in which radiographic evidence of thromboembolic events was obtained during germ cell tumor diagnosis. There was no evidence of coagulation factor abnormalities or contributory procedures or drugs in either patient. We used anticoagulation therapy for thrombolysis in one patient, but in the other, the thromboembolism resolved spontaneously.
Thromboembolism; Germ cell tumor; Chemotherapy
In Korea, cord blood banking projects have been developed since 1996, and the 1st successful cord blood transplant was performed in 1998. Recently, “Cord Blood Management and Research Act” was legislated in 2010, and has been come into effect on July 1st, 2011. This review focuses the backgrounds, aims, and legislation process as well as principal articles in this act.
Cord blood; Act
BRCA1; p300; CARM1; DNA damage; protein methylation; p21; Gadd45; cell cycle; apoptosis; cancer
The superior shoulder suspensory complex (SSSC) is an extremely important structure composed of a ring of bone and soft tissues at the superior aspect of the shoulder. Double disruption leads to instability of the construct and usually requires operative treatment. Triple disruption of the SSSC is extremely rare and is encountered in high-energy trauma cases often in association with other injuries. The authors experienced a case of triple disruption involving the acromion, coracoid process, and acromioclavicular separation. This type of SSSC disruption is unlikely to have been caused by a single impact and is rather caused by multiple impacts during one traumatic event.
Superior shoulder suspensory complex; SSSC; triple disruption
The triad of rash, arthritis, and uveitis seems to be characteristic for early-onset childhood sarcoidosis. We describe an interesting case of early-onset childhood sarcoidosis coexisting enchondromatosis, which clinically masquerade as Langerhans cell histiocytosis. A 33 months old girl presented with skin rash, subcutaneous nodules with polyarthritis, and revealed the involvement of lymph nodes as well as spleen during work-up. She also presented with multiple osteolytic lesions which pathologically proven enchondromatosis. Oral prednisone was prescribed at 2 mg/kg/day for 2 months until when subcutaneous nodules and joint swellings almost disappeared, and then slowly tapered over a period of 5 months. We report an unusual case of early-onset childhood sarcoidosis presented with osteolytic bone lesions which were irrelevant to sarcoidosis.
Sarcoidosis; Polyarthritis; Enchondromatosis; Nodule; Childhood
An efficient clinical process guideline (CPG) modeling service was designed that uses an enhanced intelligent search protocol. The need for a search system arises from the requirement for CPG models to be able to adapt to dynamic patient contexts, allowing them to be updated based on new evidence that arises from medical guidelines and papers.
A sentence category classifier combined with the AdaBoost.M1 algorithm was used to evaluate the contribution of the CPG to the quality of the search mechanism. Three annotators each tagged 340 sentences hand-chosen from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) clinical guideline. The three annotators then carried out cross-validations of the tagged corpus. A transformation function is also used that extracts a predefined set of structural feature vectors determined by analyzing the sentential instance in terms of the underlying syntactic structures and phrase-level co-occurrences that lie beneath the surface of the lexical generation event.
The additional sub-filtering using a combination of multi-classifiers was found to be more effective than a single conventional Term Frequency-Inverse Document Frequency (TF-IDF)-based search system in pinpointing the page containing or adjacent to the guideline information.
We found that transformation has the advantage of exploiting the structural and underlying features which go unseen by the bag-of-words (BOW) model. We also realized that integrating a sentential classifier with a TF-IDF-based search engine enhances the search process by maximizing the probability of the automatically presented relevant information required in the context generated by the guideline authoring environment.
Knowledge Bases; Data Mining; Natural Language Processing
The aim of this study was to assess the efficacy and safety of monthly oral 150 mg ibandronate in women with postmenopausal osteoporosis (PMO).
A systematic review and meta-analysis were performed to determine treatment efficacy and safety outcomes between monthly oral 150 mg ibandronate and weekly 70 mg alendronate, daily 2.5 mg ibandronate, and a placebo.
Eight randomized controlled trials were included in this systematic review and meta-analysis. Once-monthly 150 mg ibandronate therapy was clinically comparable to weekly 70 mg alendronate, showing increased bone mineral density (BMD) in both the lumbar spine and total hip. Pooled data from two cross-over trials showed that significantly more women with PMO preferred once-monthly ibandronate therapy to once-weekly alendronate therapy (relative risk [RR], 2.422; 95% confidence interval [CI], 2.111 to 2.825; p < 1 × 10-8) and found the monthly ibandronate regimen more convenient than the weekly alendronate regimen (RR, 3.096; 95% CI, 2.622 to 3.622; p < 1 × 10-8). Monthly 150 mg ibandronate therapy resulted in a significantly higher change in BMD of the lumbar spine than with the placebo. A once monthly 150 mg regimen produced greater increases in lumbar spine, total hip, femoral neck, and trochanter BMD than daily treatment, with a similar incidence of adverse events between the groups.
Once monthly 150 mg ibandronate therapy was clinically comparable to weekly 70 mg alendronate, and patients strongly preferred the convenience of monthly ibandronate over weekly alendronate. Monthly 150 mg ibandronate was superior to, and as well tolerated as, the daily treatment.
Ibandronic acid; Efficacy; Safety; Osteoporosis; Review
Nuclear factor of activated T-cells (NFAT) proteins are, calcium-regulated transcription factors, key regulator of stimulation-dependent gene activation. In our microarray analysis for the genes expressed in human black and white hairs, NFAT2 was significantly upregulated in the white hair, compared to the black hair. The aim of this study was to investigate functional role of NFAT2 in melanogenesis. Western blot analysis was performed to investigate the expression of NFAT2 protein in B16 melanoma cells. Our data showed that NFAT2 expression was increased in the hypopigmented B16 cells, while tyrosinase and MITF expression was decreased. To investigate the potential role of NFAT2, the recombinant adenovirus expressing microRNA specific for NFAT2 was transduced into the cultured B16 melanoma cells. Consistently, inhibition of NFAT2 enhanced tyrosinase activity and melanin content. Moreover, cyclosporine A, which is known as a calcineurin inhibitor blocking NFAT activation, enhanced tyrosinase activity and melanin content. These data suggest that NFAT2 may play an important role in regulation of melanogenesis in melanocyte.
Melanogenesis; Melanocyte; B16 melanoma cells; NFAT2; Cyclosprorin A
Functioning adrenocortical oncocytomas are extremely rare and most reported patients are 40-60 yr of age. To our knowledge, only 2 cases of functioning adrenocortical oncocytomas have been reported in childhood. We report a case of functioning adrenocortical oncocytoma in a 14-yr-old female child presenting with virilization. She presented with deepening of the voice and excessive hair growth, and elevation of plasma testosterone and dehydroepiandrosterone sulfate. She had an adrenalectomy. The completely resected tumor composed predominantly of oncocytes without atypical mitosis and necrosis. A discussion of this case and a review of the literature on this entity are presented.
Adrenal Cortex Neoplasms; Adenoma, Oxyphilic; Virilism; Child
Since cord blood (CB) contains hematopoietic stem cells as well as a mixture of multipotent stem cells, CB has the ability to give rise to hematopoietic, epithelial, endothelial and neural tissues. Recently, the application of cell-based therapy using CB has expanded its clinical utility, particularly, by using autologous CB in children with refractory diseases. This review focuses clinical and pre-clinical application of CB cell-based therapy for inherited metabolic diseases as well as tissue regenerations in neonatal hypoxic-ischemic encephalopathy, cerebral palsy, and juvenile diabetes.
Cord blood; Stem cells; Regenerative medicine
Drug-induced neutropenia (DIN), particularly that in which antibiotic-dependent antineutrophil antibodies have been detected, is a rare disorder. We report the case of a child with pneumococcal pneumonia, who experienced severe neutropenia during various antibiotic treatments. We detected 4 kinds (cefotaxim, augmentin, vancomycin, and tobramycin) of antibiotic-dependent antineutrophil antibodies by using the mixed passive hemagglutination assay (MPHA) technique with this child.
Neutropenia; Antineutrophil Antibody; Anti-Bacterial Agents
Although extracellular Ca2+ entry through the voltage-dependent Ca2+ channels plays an important role in the spontaneous phasic contractions of the pregnant rat myometrium, the role of the T-type Ca2+ channels has yet to be fully identified. The aim of this study was to investigate the role of the T-type Ca2+ channel in the spontaneous phasic contractions of the rat myometrium. Spontaneous phasic contractions and [Ca2+]i were measured simultaneously in the longitudinal strips of female Sprague-Dawley rats late in their pregnancy (on day 18~20 of gestation: term=22 days). The expression of T-type Ca2+ channel mRNAs or protein levels was measured. Cumulative addition of low concentrations (<1 µM) of nifedipine, a L-type Ca2+ channel blocker, produced a decrease in the amplitude of the spontaneous Ca2+ transients and contractions with no significant change in frequency. The mRNAs and proteins encoding two subunits (α1G, α1H) of the T-type Ca2+ channels were expressed in longitudinal muscle layer of rat myometrium. Cumulative addition of mibefradil, NNC 55-0396 or nickel induced a concentration-dependent inhibition of the amplitude and frequency of the spontaneous Ca2+ transients and contractions. Mibefradil, NNC 55-0396 or nickel also attenuated the slope of rising phase of spontaneous Ca2+ transients consistent with the reduction of the frequency. It is concluded that T-type Ca2+ channels are expressed in the pregnant rat myometrium and may play a key role for the regulation of the frequency of spontaneous phasic contractions.
Calcium channels; Nickel; Mibefradil; NNC 55-0396; Spontaneous contractility
Soft tissue defects of the posterior heel of the foot present difficult reconstructive problems. This paper reports the authors' early experience of five patients treated with a lateral calcaneal artery adipofascial flap.
Between 2003 and 2007, five patients (3 males and 2 females) with soft-tissue defects over the posterior heel underwent a reconstruction using a lateral calcaneal artery adipofascial flap and a full-thickness skin graft. The flap sizes ranged from 3.5 × 2.5 cm to 5.5 × 4.0 cm.
All five flaps survived completely with no subsequent breakdown of the grafted skin, even after regularly wearing normal shoes. The adipofascial flap donor sites were closed primarily in all patients.
Lateral calcaneal artery adipofascial flaps should be included in the surgical armamentarium to cover difficult wounds of the posterior heel of the foot. These flaps do not require the sacrifice of a major artery to the leg or foot, they are relatively thin with minimal morbidity at the donor site, and leave a simple linear scar over the lateral aspect of the foot.
Foot; Posterior heel; Soft tissue defect; Lateral calcaneal artery adipofascial flap
To report the incidence of dacryocystoceles detected by prenatal ultrasonography (US) and their postnatal outcomes and to determine the factors associated with the postnatal persistence of dacryocystoceles at birth.
We retrospectively reviewed the prenatal US database at our institution for the period between January 2012 and December 2013. The medical records of women who had fetuses diagnosed with dacryocystocel larger than 5 mm were reviewed for maternal age, gestational age (GA) at detection, size and side of the dacryocystoceles, delivery, and postnatal information, such as GA at delivery, delivery mode, and gender of the neonate.
A total of 49 singletons were diagnosed with a dacryocystocele on prenatal US, yielding an overall incidence of 0.43%. The incidence of dacryocystoceles was the highest at the GA of 27 weeks and decreased toward term. Of the 49 fetuses including three of undeter mined gender, 25 (54%) were female. The mean GA at first detection was 31.2 weeks. The dacryocystocele was unilateral in 29 cases, with a mean maximum diameter of 7 mm. Spontaneous resolution at birth was documented in 35 out of 46 neonates (76%), including six with prenatal resolution. Multivariate analysis demonstrated that GA at delivery was a significant predictor of the postnatal persistence of dacryocystoceles (P=0.045).
The overall incidence of prenatal dacryocystoceles was 0.43%; the incidence was higher in the early third trimester and decreased thereafter. Prenatal dacryocystoceles resolved in 76% of the patients at birth, and the GA at delivery was a significant predictor of postnatal persistence.
Fetus; Ultrasonography; Congenital abnormalities; Lacrimal duct obstruction
The clinical findings of fever and skin rash with or without evidence of fluid retention, which mimic engraftment syndrome, have been observed during the pre-engraftment period in patients undergoing hematopoietic stem cell transplantation. In order to characterize this newly observed clinical syndrome called pre-engraftment syndrome (pES), we retrospectively analyzed the clinical records of 50 patients. Three out of 14 patients (23.1%) who underwent cord blood stem cell transplantation developed non-infectious fever, skin rash, and tachypnea 4-15 days prior to neutrophil engraftment. Two patients spontaneously recovered with fluid restriction and oxygen inhalation. One patient died of a complicated pulmonary hemorrhage in spite of aggressive supportive therapy and steroid treatment. Four out of 23 patients (17.4%) who underwent allogeneic bone marrow transplantation developed non-infectious fever and skin rash 4 to 5 days prior to neutrophil engraftment. All four of these patients recovered with only steroid treatment. These characteristic findings were not observed in patients who had undergone autologous peripheral blood stem cell transplantation. Interestingly, the speed of neutrophil engraftment was significantly faster for the patients suffering from pre-engraftment syndrome. The close observation and further pathophysiological research are required to better understand this syndrome.
Engraftment Syndrome; Hematopoietic Stem Cell Transplantation
The application of vaccine adjuvants has been vigorously studied for a diverse range of diseases in order to improve immune responses and reduce toxicity. However, most adjuvants have limited uses in clinical practice due to their toxicity.
Therefore, to reduce health risks associated with the use of such adjuvants, we developed an advanced non-toxic adjuvant utilizing biodegradable chitosan hydrogel (CH-HG) containing ovalbumin (OVA) and granulocyte-macrophage colony-stimulating factor (GM-CSF) as a local antigen delivery system.
After subcutaneous injection into mice, OVA/GM-CSF-loaded CH-HG demonstrated improved safety and enhanced OVA-specific antibody production compared to oil-based adjuvants such as Complete Freund’s adjuvant (CFA) or Incomplete Freund’s adjuvant (IFA). Moreover, CH-HG system-mediated immune responses was characterized by increased number of OVA-specific CD4+ and CD8+ INF-γ+ T cells, leading to enhanced humoral and cellular immunity.
In this study, the improved safety and enhanced immune response characteristics of our novel adjuvant system suggest the possibility of the extended use of adjuvants in clinical practice with reduced apprehension about toxic side effects.
Electronic supplementary material
The online version of this article (doi:10.1186/s12865-014-0048-x) contains supplementary material, which is available to authorized users.
Adjuvant; Chitosan; Hydrogel; Immune response