Inherited metabolic disease is rare disorders that show symptoms mainly in pediatric age and early treatment is important for preventing complications of the disease. Recent development in molecular and biochemical techniques help clinicians with proper diagnosis of patients, however, many of the disease still remain lack of effective therapeutic strategies. Better understanding on biochemical and molecular basis of pathogenesis of the disease combined with advanced medical care would provide new sight on the disease that can also improve the quality of life and long-term prognosis of patients. Traditionally, there are several modalities in the treatment of metabolic diseases depend on the biochemical basis of the disease such as diet restriction, removing or blocking the production of toxic metabolites, and stimulating residual enzyme activity. The inherited metabolic disease is not familiar for many clinicians because the diagnosis is troublesome, treatment is complicated and prognosis may not as good as expected in other diseases. Recently, new therapeutic regimens have been introduced that can significantly improve the medical care of patients with metabolic disease. Enzyme replacement therapy has showed promising efficacy for lysosomal storage disease, bone marrow transplantation is effective in some disease and gene therapy has been trying for different diseases. The new trials for treatment of the disease will give us promising insight on the disease and most clinicians should have more interest in medical progress of the metabolic disease.
Bone Marrow Transplantation ; Diagnosis ; Diet ; Enzyme Replacement Therapy ; Genetic Therapy ; Humans ; Lysosomal Storage Diseases ; Metabolic Diseases* ; Metabolism ; Prognosis ; Quality of Life

PURPOSE: To evaluate antitumor response, time to progression, and toxicities of oxaliplatin, 5- fluorouracil (5-FU), and leucovorin (LV) continuous infusion in patients with metastatic colorectal cancer who progressed during or after treatment with a 5-FU-containing regimen. MATERIALS AND METHODS: Forty-eight patients with metastatic colorectal cancer, who progressed while receiving or after discontinuing palliative chemotherapy with 5- FU-based regimen, were enrolled in this study. Treatment consisted of oxaliplatin (85 mg/m2 on day 1) as a 2-hour infusion followed by bolus 5-FU (400 mg/m2 on day 1), and 5-FU 48-hour infusion 2.4~3 g/m2 concurrently with LV 48-hour infusion 150 mg/m2, without mixing. Cycles were repeated at 2-week intervals. The dose of 5-FU was modified, depending on the hematologic toxicity profile. RESULTS: The objective response rate was 28% for 43 assessable patients (95% confidence interval, 14% to 42%), including one complete remission (2%). Seventeen additional patients (39%) had stable disease, and fourteen (33%) progressed. The median time to progression was 5.9 months and the median overall survival was 13.2 months from the start of the chemotherapy. From the 297 cycles analyzed, hematologic toxicities per course were: leukopenia; grade I 26.6%, grade II 3.4%, and grade III 0.3%, thrombocytopenia; grade I 10.8%, grade II 3.0%, grade III 1.0%, and grade IV 0.3%. The most frequent nonhematologic adverse reactions were nausea/vomiting and peripheral neuropathy, which were rated as WHO grade II in 13 patients (49%) and 11 patients (22%), respectively. CONCLUSION: This phase II study of oxaliplatin, 5-FU, and LV continuous infusion showed enhanced antitumor activity in patients with 5-FU-pretreated metastatic colorectal cancer. Overall toxicity was acceptable; neurotoxicity and bone marrow suppression constituted the dose-limiting side effects.
Bone Marrow ; Colorectal Neoplasms* ; Drug Therapy ; Fluorouracil* ; Humans ; Leucovorin* ; Leukopenia ; Peripheral Nervous System Diseases ; Thrombocytopenia

OBJECTIVE: To explore the characteristics of Shwachman-Diamond syndrome (SDS) in Chinese children in order to provide a reference for early diagnosis. METHODS: With Shwachman-Diamond syndrome, SDS, SBDS gene and inherited bone marrow failure as the keywords, the search period was set from January 2002 to October 2022. Relevant literature was retrieved from the Wanfang Database and China National Knowledge Infrastructure (CNKI) database. In addition, by using Shwachman-diamond syndrome as a keyword, the search period was also retrieved from the Web of Science, PubMed, and MEDLINE databases from January 2002 to October 2022. A child with SDS treated at the Tongji Hospital was also included. A total of 44 cases with complete clinical data were analyzed with reference to the International Standard for SDS Diagnosis. Chi-square test and t test were used for statistical analysis. Evidence-based research was carried out in the form of systematic review. The epidemiology, clinical characteristics and key points of early diagnosis of the Chinese SDS children were summarized and compared with the international data. RESULTS: The main characteristics of SDS in Chinese children were summarized as follows: The ratio of males to females was about 1.3 : 1, the median age of onset was 3 months, and the median age of diagnosis was 14 months. The first symptoms were often exocrine pancreatic insufficiency (31.8%) and granulocytopenia with infection (31.8%). According to the international consensus, the incidence rates of the three major diseases of SDS were hemocytopenia (95.4%), pancreatic disease (72.7%), and bone abnormality (40.9%). The common factors underlying SDS disease were variants of the SBDS gene (c.258+2T>C and c.183_184TA>CT), albeit there was no significant correlation between genotype and phenotype (P > 0.05). Compared with international reports, the clinical manifestations and genotypes of Chinese SDS children are different (P < 0.05). CONCLUSION The SDS children have an early age of onset and significant individual difference. It is necessary to analyze the case-related data to facilitate early recognition, diagnosis and clinical intervention.
Female ; Humans ; Male ; Bone Marrow Diseases/therapy* ; China ; East Asian People ; Exocrine Pancreatic Insufficiency/therapy* ; Shwachman-Diamond Syndrome/therapy*

Gaucher's disease (GD) is the most common inherited lysosomal storage disease, manifested by generalized accumulation of glucocerebroside in macrophages of the reticuloendothelial system due to a deficient lysosomal beta-glucocerebrosidase (GC). It is inherited by an autosomal recessive pattern in which three clinical phenotypes have been described based on the presence and severity of neurologic involvement. GD is treated possible by GC enzyme replacement therapy, allogeneic bone marrow transplantation (BMT), and gene therapy. We here report the exprience of successful allogeneic BMT in a 16-year-old female patient with GD type III which was demostrated markedly increased Gaucher cells in bone marrow and absence of GC activity in peripheral blood monocytes by FACS using 5'- pentafluorobenzoylaminofluorescein-di-beta-D-glucoside (PFBFDGlu) as substrate. Donor marrow engraftment was confirmed by chromosome analysis using microsatellite and by bone marrow examination. Assay of GC activity using FACS revealed normal level of enzyme activity. She remains alive and well after 12 months of BMT.
Adolescent ; Bone Marrow Examination ; Bone Marrow Transplantation* ; Bone Marrow* ; Enzyme Replacement Therapy ; Female ; Gaucher Disease* ; Genetic Therapy ; Glucosylceramidase ; Humans ; Lysosomal Storage Diseases ; Macrophages ; Microsatellite Repeats ; Monocytes ; Mononuclear Phagocyte System ; Phenotype ; Tissue Donors

High-dose cytotoxic therapy followed by autologous stem cell transplantation has been proposed as a novel treatment modality for severe autoimmune disease. The rationale of autologous stem cell transplantation in autoimmune diseases has been based on the autoimmune animal models that marked improvement or complete eradication of autoimmune disease after syngeneic marrow transplantation. In addition, several clinical data showed that allogeneic marrow transplantation has been reported to eradicate concurrent autoimmune disease, suggesting that high-dose cytotoxic therapy may be sufficient to eradicate autoaggressive lymphocytes. Peripheral blood stem cell transplantation is widely used compared to bone marrow transplantation due to rapid marrow recovery and less treatment-related mortality. Recently, immunoablative high-dose cytotoxic therapy without stem-cell rescue also can induce complete remission in patients with refractory, severe autoimmune disease. Although several clinical data of autologous stem transplantation can achieve durable remission in severe autoimmune disease, long-term efficacy has not been fully determined yet. Further studies are needed to assess the exact role of stem cell transplantation in the treatment of severe autoimmune disease through well-designed clinical trials.
Autoimmune Diseases* ; Bone Marrow ; Bone Marrow Transplantation ; Drug Therapy* ; Humans ; Lymphocytes ; Models, Animal ; Mortality ; Peripheral Blood Stem Cell Transplantation ; Stem Cell Transplantation* ; Stem Cells*

PURPOSE: Whole liver transplantation has limitation including donor shortage and fatal surgical complications. Hepatocyte transplantation, which is simpler and less expensive than whole liver transplantation, allows the use of living related donors, permits the use of a single donor organ for multiple recipients, and makes possible the cryopreser-vation of hepatocytes for future use. However, hepatocytes have limitation of proliferation and lose their property during culture period. To over come this problems, here we performed differentiation of bone marrow derived mesenchymal stem cells into hepatocytes. METHODS: Human bone marrow cells were harvested from posterior iliac spine of male and then mononuclear cells were obtained by Ficoll-Paque density-gradient centrifuge and plated in tissue culture flasks. For hepatogenic differentiation, we used modified Kuan-Der Lee's method. After differentiation, hepatocytes were collected and RT-PCR and PAS stain analysis were performed. RESULTS: After 5 weeks of cultivation period, mesenchymal stem cells showed cuboidal morphology and contained abundant granules in the cytoplasm. RT-PCR analysis showed increased expression of hepatocyte-specific marker genes (albumin,CK18, PERCK, CPS). Undifferentiated MSCs were not stained with PAS and differentiated hepatocytes from human MSCs stained with PAS indicating that hepatocytes contained glycogen in the cytoplasm. CONCLUSION: Hepatocyte transplantation could be one of the most effective treatments for chronic liver disease. However, hepatocyte has several disadvantages and problems. For alternative cell therapy sources, human bone marrow derived MSCs are considered as transplantable cells. Human MSCs are able to differentiate into functional hepatocytes in vitro and can be a possible cell transplantation source for chronic liver disease patients. Further studies should be done for differentiating human MSCs to hepatocytes in vivo condition.
Bone Marrow ; Bone Marrow Cells ; Cell Transplantation ; Cell- and Tissue-Based Therapy ; Cytoplasm ; Glycogen ; Hepatocytes* ; Humans* ; Liver Diseases ; Liver Transplantation ; Male ; Mesenchymal Stromal Cells* ; Spine ; Tissue Donors ; Transplants

Reactivation of hepatitis B virus (HBV) infection has been known to be a serious complication of immunosuppressive or cytotoxic chemotherapy in HBV carriers or chronic hepatitis B patients. We report here a 25-year-old woman who has severe aplastic anemia and chronic hepatitis B underwent successful allogeneic bone marrow transplantation (BMT) with prophylactic lamivudine treatment and showed no evidence of reactivation of hepatitis B, HBV DNA elevation, or liver dysfunction. This result suggests that prophylactic administration of lamivudine to a BMT recipient of chronic hepatitis B might be a safe and promising measure to prevent fatal liver dysfunction.
Adult ; Anemia, Aplastic* ; Bone Marrow Transplantation* ; Bone Marrow* ; DNA ; Drug Therapy ; Female ; Hepatitis B ; Hepatitis B virus ; Hepatitis B, Chronic ; Humans ; Lamivudine* ; Liver Diseases

BACKGROUNDBone marrow cell transplantation has been shown to induce angiogenesis and thus improve ischemic disease. This study evaluated the effect of bone marrow mononuclear cell (BM-MNCs) implantation on neovascularization in rats with ischemic bile duct.

METHODSWe established an animal model for ischemic biliary stenosis by clamping manipulation. There were 10 rats in each group: BM-MNCs implantation group, control group and normal group. Rat femur BM-MNCs were isolated using density gradient centrifugation. BM-MNCs or phosphate buffered saline were injected into three points around bile duct tissue in the three groups (25 µl/point). Control rats received injections of saline under similar conditions. At the 21 days after operation, cholangiography was performed. Differentiation of the engrafted cells and capillary density in the bile duct were analyzed by immunohistochemical staining.

RESULTSEngrafted cells could differentiate into endothelial cells. The stricture rate in the implantation group was 40%, significantly lower than that in the control group (100%). The capillary density in the implantation group was significantly higher than in the control group or the normal group.

CONCLUSIONSThe implantation of BM-MNCs induced neovascularization in the ischemic bile duct. It improved the blood supply of the ischemic bile duct to prevent or decrease biliary ischemic stricture.

Animals ; Bile Duct Diseases ; therapy ; Body Weight ; Bone Marrow Transplantation ; methods ; Immunohistochemistry ; Ischemia ; therapy ; Male ; Rats ; Transplantation, Autologous ; methods

BACKGROUND: Loss of bone mass is usually detected after bone marrow transplantation (BMT), especially during the early post-transplant period. But little is known about the long-term effects of BMT on bone mineral metabolism. METHODS: We have investigated prospectively 12 patients undergoing BMT (4 autologous, 8 allogeneic) for hematologic diseases (8 leukemia, 3 SAA, 1 MDS). Serum concentrations of calcium, phosphorus, creatinine, gonadotropins, sex hormones and bone turnover markers (osteocalcin and ICTP) were measured. The samples were collected before BMT and 1, 2, 3, 4, and 12 weeks, 6 months and 1, 2 years thereafter. Bone mineral density (BMD) was measured with DEXA (Dual Energy X-ray Absorptiometry) before BMT, 1 year and 2 year after BMT. In patients with amenorrbea, hormone replacement therapy was started from around 1 year after BMT RESULTS: 1. The mean bone loss in the lumbar spine, calculated as the percent change from the baseline to the level at 1 year and 2 year was 7.3% and 1.9%, respectively. The mean bone loss in the total proximal femur from the baseline to the level at 1 year and 2 year was 8.0% and 8.3% respectively. 2. The serum ICTP increased progressively until four weeks after BMT. Thereafter, it decreased gradually to reach basal values after one year and thereafter no more change until 2 year. Serum osteocalcin decreased progressively until three weeks after BMT. After that, it increased and reached basal values after 3 months. Osteocalcin increased at 6 month transiently but thereafter, it decreased to the level of slightly above basal value at 2 year. 3. Patients who were treated with TBI or pateints with GVHD had a tendency of lower BMD at l year and 2 year after BMT than those of patients without TBI or GVHD. 4. Eight out of nine women went into a menopausal state immediately after BMT and remained amenorrhea, evidenced by high gonadotropins and low estradiol levels. In contrast to women, gonadotropins and testosterone levels were not changed significantly in men after BMT. CONCLUSION: The rapid impairment of bone formation and the increase in bone resorption, as shown by the biochemical markers in this study, might play a role in bone loss after BMT. The efficacy of HRT for the correction of hypogonadism and bone loss was evidenced by 2 year BMD which was much more increased compared to 1 year BMD, especially in vertebra.
Amenorrhea ; Biomarkers ; Bone Density ; Bone Marrow Transplantation* ; Bone Marrow* ; Bone Resorption ; Calcium ; Creatinine ; Estradiol ; Female ; Femur ; Gonadal Steroid Hormones ; Gonadotropins ; Hematologic Diseases ; Hormone Replacement Therapy ; Humans ; Hypogonadism ; Leukemia ; Male ; Metabolism* ; Osteocalcin ; Osteogenesis ; Phosphorus ; Prospective Studies* ; Spine ; Testosterone

Recent experimental studies showed that angiogenesis can be stimulated by administration of angiogenic growth factors or supplementation of angiogenic stem cells. After extensive investigation in preclinical studies and recent clinical trials, therapeutic angiogenesis has been established as a potential method to salvage ischemic myocardial and limb disease patients who have no therapeutic options in current medicine. The safety and tolerability of therapeutic angiogenesis by gene transfer has been demonstrated in phase I clinical trials, and although early phase II studies of angiogenic gene therapy demonstrated limited evidence of efficacy, adequately powered, randomized, placebo-controlled phase II and III clinical trials will determine the utility of therapeutic angiogenesis by gene transfer. Supplement-side therapeutic angiogenesis by administration of angiogenic stem cells, especially endothelial progenitor cells from bone marrow, showed marked efficacy in both ischemic myocardial and limb disease in early phase II clinical trials. Endothelial progenitor cells not only support angiogenesis, but are also suggested to transdifferentiate into cardiomyocytes which might replace the lost myocardium. This review focuses on the use of angiogenic genes, protein, or adult stem cells for the treatment of ischemic cardiovascular disease and contrasts how far we have come in a short time with how far we still need to go before therapeutic angiogenesis becomes routine in cardiovascular medicine.
Adult Stem Cells ; Bone Marrow ; Cardiovascular Diseases* ; Extremities ; Genetic Therapy ; Humans ; Intercellular Signaling Peptides and Proteins ; Myocardium ; Myocytes, Cardiac ; Stem Cells