Diabetes Mellitus after Hematopoietic Stem Cell Transplantation

ObjectiveTo review the current literature on posttransplant diabetes mellitus after hematopoietic stem cell transplantation, including its epidemiologic features, transplant-related risk factors, and treatment.MethodsA literature search was conducted in PubMed for articles on diabetes mellitus after hematopoietic stem cell transplantation and effects of immunosuppressants on glucose metabolism.ResultsWithin 2 years after hematopoietic stem cell transplantation, up to 30% of patients may have diabetes. Although some of these cases resolve, the rates of diabetes and metabolic syndrome remain elevated in comparison with those in the nontransplant patient population during long-term follow-up. Traditional risk factors for diabetes as well as features related to the transplantation process, including immunosuppressive medications, are associated with posttransplant diabetes. Cardiovascular risk also appears to be increased in this population. Limited data are available on hypoglycemic agents for posttransplant diabetes; thus, treatment decisions must be based on safety, efficacy, and tolerability, with consideration of each patient’s transplant-related medications and comorbidities.ConclusionTreatment of diabetes mellitus in patients who have undergone hematopoietic stem cell transplantation necessitates attention to the posttransplant medication regimen and clinical course. Although no guidelines specific to treatment of posttransplant diabetes in this patient population currently exist, treatment to goals similar to those for nontransplant patients with diabetes should be considered in an attempt to help reduce long-term morbidity and mortality. (Endocr Pract. 2010;16:699-706)     

Detection of Lipoprotein X (LpX): A challenge in patients with severe hypercholesterolaemia

BackgroundLipoprotein X (LpX) is an abnormal lipoprotein fraction, which can be detected in patients with severe hypercholesterolaemia and cholestatic liver disease. LpX is composed largely of phospholipid and free cholesterol, with small amounts of triglyceride, cholesteryl ester and protein. There are no widely available methods for direct measurement of LpX in routine laboratory practice. We present the heterogeneity of clinical and laboratory manifestations of the presence of LpX, a phenomenon which hinders LpX detection.MethodsThe study was conducted on a 26-year-old female after liver transplantation (LTx) with severely elevated total cholesterol (TC) of 38 mmol/L and increased cholestatic liver enzymes. TC, free cholesterol (FC), cholesteryl esters (CE), triglycerides, phospholipids, HDL-C, LDL-C, and apolipoproteins AI and B were measured. TC/apoB and FC:CE ratios were calculated. Lipoprotein electrophoresis was performed using a commercially available kit and laboratory-prepared agarose gel.ResultsCommercially available electrophoresis failed to demonstrate the presence of LpX. Laboratory-prepared gel clearly revealed the presence of lipoproteins with γ mobility, characteristic of LpX. The TC/apoB ratio was elevated and the CE level was reduced, confirming the presence of LpX. Regular lipoprotein apheresis was applied as the method of choice in LpX disease and a bridge to reLTx due to chronic liver insufficiency.ConclusionsThe detection of LpX is crucial as it may influence the method of treatment. As routinely available biochemical laboratory tests do not always indicate the presence of LpX, in severe hypercholesterolaemia with cholestasis, any discrepancy between electrophoresis and biochemical tests should raise suspicions of LpX disease.     

Expanded umbilical cord blood T cells used as donor lymphocyte infusions after umbilical cord blood transplantation

BackgroundUmbilical cord blood (UCB) is an alternative graft source for hematopoietic stem cell transplantation and has been shown to give results comparable to transplantation with other stem cell sources. Donor lymphocyte infusion (DLI) is an effective treatment for relapsed malignancies after hematopoietic stem cell transplantation. However, DLI is not available after UCB transplantation.MethodsIn this study, in vitro–cultured T cells from the UCB graft were explored as an alternative to conventional DLI. The main aim was to study the safety of the cultured UCB T cells used as DLI because such cell preparations have not been used in this context previously. We also assessed potential benefits of the treatment.ResultsThe cultured UCB T cells (UCB DLI) were given to 4 patients with mixed chimerism (n = 2), minimal residual disease (n = 1) and graft failure (n = 1). No adverse reactions were seen at transfusion. Three of the patients did not show any signs of graft-versus-host disease (GVHD) after UCB DLI, but GVHD could not be excluded in the last patient. In the patient with minimal residual disease treated with UCB DLI, the malignant cell clone was detectable shortly before infusion but undetectable at treatment and for 3 months after infusion. In 1 patient with mixed chimerism, the percentage of recipient cells decreased in temporal association with UCB DLI treatment.ConclusionsWe saw no certain adverse effects of treatment with UCB DLI. Events that could indicate possible benefits were seen but with no certain causal association with the treatment.     

Magnetically empowered bone marrow cells as a micro-living motor can improve early hematopoietic reconstitution

Background aimsBone marrow-derived hematopoietic stem cell transplantation/hematopoietic progenitor cell transplantation (HSCT/HPCT) is widely used and one of the most useful treatments in clinical practice. However, the homing rate of hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs) by routine cell transfusion is quite low, influencing hematopoietic reconstitution after HSCT/HPCT.MethodsThe authors developed a micro-living motor (MLM) strategy to increase the number of magnetically empowered bone marrow cells (ME-BMCs) homing to the bone marrow of recipient mice.ResultsIn the in vitro study, migration and retention of ME-BMCs were greatly improved in comparison with non-magnetized bone marrow cells, and the biological characteristics of ME-BMCs were well maintained. Differentially expressed gene analysis indicated that ME-BMCs might function through gene regulation. In the in vivo study, faster hematopoietic reconstitution was observed in ME-BMC mice, which demonstrated a better survival rate and milder symptoms of acute graft-versus-host disease after transplantation of allogeneic ME-BMCs.ConclusionsThis study demonstrated that ME-BMCs serving as MLMs facilitated the homing of HSCs/HPCs and eventually contributed to earlier hematopoietic reconstitution in recipients. These data might provide useful information for other kinds of cell therapies.     

Endocrine Complications in Patients with Gvhd

Objective: Graft-versus-host disease (GVHD) is an immune phenomenon that occurs in 30 to 70% of patients after allogeneic hematopoietic stem cell transplantation (HST). Chronic GVHD is a state of immune dysregulation wherein, depending on the severity and organ involved, patients may require prolonged treatment with additional or higher corticosteroids and other immunosuppressive agents. The objective of this study was to review the endocrine manifestations following HST that can arise as a consequence of the primary disease or its treatment, including chemotherapeutic agents, corticosteroids, radiation, or GVHD.Methods: We performed a narrative review of GVHD after HST. An English-language search for relevant studies was conducted on PubMed from inception to August 1, 2018, using the following search terms: “endocrine complications,” “bone marrow transplantation,” “graft-versus-host disease,” and “GVHD.” The reference lists of relevant studies were also reviewed.Results: Chronic GVHD may be associated with considerable pediatric growth impairment and may also contribute to thyroid gland dysfunction and thyroid cancer. These patients may also be at increased risk for low bone mineral density, reduced fertility, metabolic syndrome, and suppression of the pituitary-adrenal axis with adrenal insufficiency.Conclusion: This review indicates the importance of monitoring, diagnosing, and properly treating the endocrine complications in this population. More studies are needed to investigate the independent impact of GVHD on the endocrine system and treatment for complications.Abbreviations: BMD = bone mineral density; GH = growth hormone; GVHD = graft-versus-host disease; HST = hematopoietic stem cell transplantation; IGF-1 = insulin-like growth factor 1     

Intra-bone marrow transplantation of human CD34+ cells into NOD/LtSz-scid IL-2rγnull mice permits multilineage engraftment without previous irradiation

Background aimsNon-irradiated immunodeficient recipients provide the best physiologic setting for revealing hematopoietic stem cell (HSC) functions after xenotransplantion. An approach that efficiently permits the detection of human hematopoietic repopulating cells in non-irradiated recipients is therefore highly desired.MethodsWe compared side-by-side the ability to reconstitute hematopoiesis via intra-bone marrow transplantation (IBMT) in three commonly used mouse strains avoiding previous irradiation.ResultsNon-irradiated NOD/SCID and NOD/SCID (β2m?/? mouse strains prevent engraftment even after IBMT. In contrast, combining the robustness of the NOD/SCID IL-2Rγ?/? recipient with the sensitivity of IBMT facilitates the detection, without previous host irradiation, of human SCID-repopulating cells 10 weeks after transplantation. The level of chimerism averaged 14% and multilineage engraftment (lymphoid dominant) was observed consistently in all mice. Analysis of injected and non-injected bones, spleen and peripheral blood demonstrated that engrafting cells were capable of in vivo migration and expansion.ConclusionsCombining the robustness of the NOD/SCID IL-2Rγ?/? mouse strain with the sensitivity of IBMT strongly facilitates long-term multilineage engraftment and migration for human CD34⁺ cells without the need for previous irradiation.     

Disease-Corrected Hepatocyte-Like Cells from Familial Hypercholesterolemia-Induced Pluripotent Stem Cells

The generation of human induced pluripotent stem cells (hiPSCs) from an individual patient provides a unique tool for disease modeling, drug discovery, and cell replacement therapies. Patient-specific pluripotent stem cells can be expanded in vitro and are thus suitable for genetic manipulations. To date, several genetic liver disorders have been modeled using patient-specific hiPSCs. Here, we present the generation of corrected hepatocyte-like cells (HLCs) from hiPSCs of a familial hypercholesterolemia (FH) patient with a homozygous mutation in the low-density lipoprotein receptor (LDLR) gene. We generated hiPSCs from a patient with FH with the mutated gene encoding a truncated non-functional receptor. In order to deliver normal LDLR to the defective cells, we used a plasmid vector carrying the normal receptor ORF to genetically transform the hiPSCs. The transformed cells were expanded and directed toward HLCs. Undifferentiated defective hiPSCs and HLCs differentiated from the defective hiPSCs did not have the ability to uptake labeled low-density lipoprotein (LDL) particles. The differentiated transformed hiPSCs showed LDL-uptake ability and the correction of disease phenotype as well as expressions of hepatocyte-specific markers. The functionality of differentiated cells was also confirmed by indo-cyanine green (ICG) uptake assay, PAS staining, inducible cyp450 activity, and oil red staining. These data suggest that hiPSC technology can be used for generation of disease-corrected, patient-specific HLCs with potential value for disease modeling and drug discovery as well as cell therapy applications in future.     

Unmasking of Type III Hyperlipoproteinemia by Hypothyroidism: A Dramatic Illustration of Altered Lipoprotein Metabolism in a Postpartum Woman

ObjectiveTo illustrate the potential abnormalities in lipoprotein metabolism associated with type III hyperlipoproteinemia and the modulation of their clinical expression by thyroid hormone and estrogenic status.MethodsAn illustrative case, with associated clinical and laboratory data, is presented, and relevant clinical and pathophysiologic studies from the literature are reviewed.ResultsA 35-year-old woman, at 7 months after delivery of her first child, presented to her family physician with a complaint of painful eruptions on the palms of her hands. On evaluation, she was found to have new hypothyroidism and severe hypertriglyceridemia (> 1,569 mg/dL). Thyroxine replacement was initiated, and she was referred to the lipid clinic. When seen in the lipid clinic shortly thereafter, her triglyceride level had normalized, but her low-density lipoprotein (LDL) fraction was strikingly elevated (representing a combination of elevated intermediate-density lipoprotein and LDL cholesterol). On physical examination, palmar xanthomas were noted, suggestive of type III hyperlipoproteinemia. This diagnosis was further supported by homozygosity at the apolipoprotein E (apo E) gene locus for the apo E2 allele implicated in this condition. Ultimately, with attainment of euthyroidism in the subsequent weeks, the lipid profile normalized, with the LDL cholesterol concentration particularly reduced at 55 mg/dL.Conclusion: Clinical expression of type III hyperlipoproteinemia necessitates interaction between an underlying genetic defect of lipoprotein metabolism (apo E2 homozygosity) and a secondary metabolic insult such as, in the current case, hypothyroidism and possibly breast-feeding-mediated hypoestrogenemia. As such, in patients with type III hyperlipoproteinemia, it is essential to search for exacerbating factors, particularly because the amelioration of such factors may rectify the effects of the underlying dyslipidemia. (Endocr Pract. 2005;11:394-398)     

Commentary on the Role of Insulin Sensitizers on Cardiovascular Risk Factors in Polycystic Ovarian Syndrome: A Meta-Analysis

Abbreviations: CIMT = carotid intima media thickness CVD = cardiovascular disease LDL = low-density lipoprotein PCOM = polycystic ovarian morphology PCOS = polycystic ovary syndrome TZDs = thiazolidenediones     

American Association Of Clinical Endocrinologists And American College Of Endocrinology Guidelines For Management Of Dyslipidemia And Prevention Of Cardiovascular Disease - Executive Summary

Objective: The development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs).Methods: Each Recommendation is based on a diligent review of the clinical evidence with transparent incorporation of subjective factors.Results: The Executive Summary of this document contains 87 Recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 (10.3%) are Grade D. These detailed, evidence-based recommendations allow for nuance-based clinical decision making that addresses multiple aspects of real-world medical care. The evidence base presented in the subsequent Appendix provides relevant supporting information for Executive Summary Recommendations. This update contains 695 citations of which 202 (29.1 %) are evidence level (EL) 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 237 (34.1%) are EL 4 (no clinical evidence).Conclusion: This CPG is a practical tool that endocrinologists, other healthcare professionals, regulatory bodies and health-related organizations can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of patients with various lipid disorders. These recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously recommended and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to patients with diabetes, familial hypercholesterolemia, women, and pediatric patients with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions.AbbreviationsA1C = hemoglobin A1CACE = American College of EndocrinologyACS = acute coronary syndromeAHA = American Heart AssociationASCVD = atherosclerotic cardiovascular diseaseATP = Adult Treatment Panelapo = apolipoproteinBEL = best evidence levelCKD = chronic kidney diseaseCPG = clinical practice guidelinesCVA = cerebrovascular accidentEL = evidence levelFH = familial hypercholesterolemiaHDL-C = high-density lipoprotein cholesterolHeFH = heterozygous familial hypercholesterolemiaHIV = human immunodeficiency virusHoFH = homozygous familial hypercholesterolemiahsCRP = high-sensitivity C-reactive proteinLDL-C = low-density lipoprotein cholesterolLp-PLA₂ = lipoprotein-associated phospholipase A₂MESA = Multi-Ethnic Study of AtherosclerosisMetS = metabolic syndromeMI = myocardial infarctionNCEP = National Cholesterol Education ProgramPCOS = polycystic ovary syndromePCSK9 = proprotein convertase subtilisin/kexin type 9T1DM = type 1 diabetes mellitusT2DM = type 2 diabetes mellitusTG = triglyceridesVLDL-C = very low-density lipoprotein cholesterol     

Increase of Classic and Nonclassic Cardiovascular Risk Factors in Patients with Acromegaly

ObjectiveTo evaluate the prevalence of classic and nonclassic cardiovascular risk factors in patients with acromegaly.MethodsSixty-two patients with acromegaly (50 with active disease and 12 with controlled acromegaly) and 36 healthy persons (the control group) underwent measurement of lipids, fasting plasma glucose, homeostasis model assessment of insulin resistance (HOMA-IR) index, Lp(a), high-sensitivity C-reactive protein (hsCRP), homocysteine, and variables primarily related to thrombogenesis (fibrinogen, antithrombin III, protein C, and protein S).ResultsIn comparison with control subjects, patients with active acromegaly had significantly higher mean values of fasting plasma glucose, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein (VLDL) cholesterol, triglycerides, Lp(a), HOMA-IR, and fibrinogen as well as lower mean levels of high-density lipoprotein cholesterol and protein S. In both groups, homocysteine, antithrombin III, protein C, and hsCRP levels were similar. Moreover, patients with active acromegaly, in comparison with those who had controlled acromegaly, presented with significantly higher values of fasting plasma glucose, HOMA-IR, triglycerides, VLDL cholesterol, Lp(a), and fibrinogen, whereas hsCRP and protein S were significantly lower. Finally, low levels of high-density lipoprotein cholesterol and protein S as well as elevated values of VLDL cholesterol, triglycerides, HOMA-IR, and fasting plasma glucose were more prevalent in patients with active acromegaly than in the other groups.ConclusionOur findings demonstrate that, in comparison with control subjects and patients with controlled acromegaly, patients with active acromegaly had a higher frequency of classic and nonclassic cardiovascular risk factors. These findings are potentially very important because acromegaly is associated with a 2- to 3-fold increase in mortality rate, predominantly related to cardiovascular disease. (Endocr Pract. 2007;13:363-372)     

HMG-CoA reductase inhibitor augments the serum total cholesterol-lowering effect of human adipose tissue-derived multilineage progenitor cells in hyperlipidemic homozygous Watanabe rabbits

Familial hypercholesterolemia (FH) is an autosomal codominant disease characterized by high concentrations of proatherogenic lipoproteins secondary to deficiency in low-density lipoprotein (LDL) receptor. We reported recently the use of in situ stem cell therapy of human adipose tissue-derived multilineage progenitor cells (hADMPCs) in lowering serum total cholesterol in the homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of homozygous FH. Here we demonstrate that pravastatin, an HMG-CoA reductase inhibitor, augmented the cholesterol-lowering effect of transplanted hADMPCs and enhanced LDL clearance in homozygous WHHL rabbit. The results suggest the potential beneficial effects of in situ stem cell therapy in concert with appropriately selected pharmaceutical agents, in regenerative medicine.     

A double mutant LDL receptor allele in a Cypriot family with heterozygous familial hypercholesterolemia

Two novel mutations Q363X and D365E were identified in the low-density lipoprotein receptor gene in a Cypriot patient with heterozygous familial hypercholesterolemia. Restriction enzyme analysis of the index case and seven of her family members, by using AvaII and PvuII respectively, demonstrated that the two exon 8 mutations are transmitted in cis within the family. The disease phenotype is probably caused by the stop-363 mutation; this would result in a truncated protein that would probably be rapidly degraded in the extracellular space. Received: 15 August 1996 / Accepted: 10 February 1997     

Advances in Lipid Testing and Management in Patients with Diabetes Mellitus

ObjectiveTo review the pathophysiologic basis for the classic phenotype associated with diabetic dyslipidemia, discuss recent advances in lipid and lipoprotein testing for risk assessment and lipid therapy monitoring, and summarize a systematic approach to the clinical management of diabetic dyslipidemia.MethodsWe review the pertinent literature, including treatment guidelines and results of major clinical trials, and discuss the effectiveness of various pharmacologic interventions for management of lipid levels in patients with diabetes.ResultsThe incidence and prevalence of type 2 diabetes mellitus continue to escalate globally at alarming rates. Diabetes predisposes to multiple microvascular and macrovascular complications, including cardiovascular disease, the number 1 cause of mortality in the United States. The third report of the National Cholesterol Education Program Adult Treatment Panel in 2001 identified diabetes as a coronary heart disease (CHD) risk equivalent, in light of the evidence that CHD risk in persons with diabetes is similar to that of nondiabetic persons with established CHD. Diabetic dyslipidemia is characterized by a constellation of lipid derangements—hypertriglyceridemia, a low concentration of high-density lipoprotein cholesterol (HDL-C), and a high concentration of small, dense low-density lipoprotein (LDL) particles—that accelerate the progression of atherosclerotic disease and the development of atherothrombotic events.ConclusionStatin trials have demonstrated significant reductions in morbidity and mortality from cardiovascular diseases, including in patients with diabetes. Nevertheless, many patients who achieve their LDL cholesterol (LDL-C) goal still have residual CHD risk. Diabetic dyslipidemia contributes to this residual risk because of the increased concentration of atherogenic apolipoprotein B-containing lipoproteins that can persist despite normalized LDL-C levels and low HDL-C levels. Recent clinical trials emphasize the importance of intensive lipid lowering to achieve recommended goals for LDL-C, non-HDL-C, and apolipoprotein B. (Endocr Pract. 2009;15:641-652)     

Lipid Abnormalities in Patients Infected With HumanImmunodeficiency Virus

ObjectiveTo review the types, mechanisms, clinical implications, and management of lipid abnormalities associated with human immunodeficiency virus (HIV) infection and its treatment.MethodsReview of the relevant literature using MEDLINE data sources from 1985 to February 2008, endocrinology textbooks, and hand-searching of cross-references from original articles and reviews. Clinical trials, animal studies, in vitro studies, case reports, reviews, and guidelines of major medical associations were included.ResultsAdvanced stages of HIV infection are characterized by low plasma levels of total cholesterol, highdensity lipoprotein cholesterol, low-density lipoprotein cholesterol, and elevated triglycerides. Antiretroviral agents can exert negative effects on lipids that vary substantially between different drug classes and between individual drugs within each class. Prospective studies suggest that the use of protease inhibitors may be associated with increased risk of myocardial infarction that is mediated in part by dyslipidemia. Target levels of plasma lipids and management of HIV–related dyslipidemia generally follow the same guidelines as in the general population. However, dyslipidemia in this setting is often difficult to control with a single lipid-lowering agent, and potentially serious drug interactions may exist between some statins, such as simvastatin, and protease inhibitors.ConclusionsPlasma lipids should be measured in all patients infected with HIV before and 3 to 4 months after starting antiretroviral drugs. Statins are the initial drugs of choice in most patients. The concomitant use of statins and antiretroviral drugs should take into account various interactions between these agents. (Endocr Pract. 2008;14:492-500)     

Acute Liver Failure with Thyrotoxicosis Treated with Liver Transplantation

ObjectiveWe describe a young woman with previously undiagnosed thyrotoxicosis who presented with acute liver failure (ALF).MethodsWe present a case report and review the relevant literature.ResultsAn extensive evaluation excluded possible causes of ALF other than thyrotoxicosis. The management of thyrotoxicosis posed several unique challenges in the setting of ALF, particularly because we did not want to use potentially hepatotoxic thionamides. The patient was treated with prednisone and propranolol and was started on potassium iodide when she was listed for liver transplantation. She underwent an uncomplicated liver transplant and subsequent thyroidectomy and is doing well.ConclusionThis well-characterized case describes thyrotoxicosis as a possible cause of ALF after thoroughly excluding other possible causes and illustrates the challenges of simultaneously managing both disorders. To our knowledge, this is the first report of ALF possibly resulting from untreated thyrotoxicosis that was successfully treated with liver transplantation. (Endocr Pract. 2013;19:e57-e60)     

Diabetes: A Cardiac Condition Manifesting as Hyperglycemia

ObjectiveTo investigate the reasons for the increased risk of cardiovascular events and mortality in individuals with type 2 diabetes mellitus.MethodsFrom January 1990 to March 2008, literature relevant to low-density lipoprotein (LDL) and highdensity lipoprotein (HDL) cholesterol, hemoglobin A1c, acute hyperglycemia, postprandial hyperglycemia, systolic blood pressure, insulin resistance, endothelial dysfunction, microalbuminuria, diabetic cardiomyopathy, left ventricular hypertrophy, function inhibitors of the renin-angiotensin system and sympathetic nervous system, statins, and antiplatelet therapy as related to cardiac events and mortality in type 2 diabetic patients was reviewed.ResultsIncreased numbers of cardiac events and mortality in type 2 diabetes are associated with low HDL and high LDL cholesterol, high hemoglobin A1c, and high systolic blood pressure. Acute hyperglycemia, postprandial hyperglycemia, and possibly use of traditional sulfonylureas also increase incidence of cardiac events and mortality. The presence of microalbuminuria signifies endothelial dysfunction and an increased risk of cardiac events. Hypertension should be treated to goals that are lower in the diabetic patient with multiple therapies, which include suppressors of the renin-angiotensin and sympathetic nervous systems. Decreased improvement in outcomes for the diabetic patient with cardiovascular disease may be accounted for by the failure to treat insulin resistance and ventricular dysfunction. The high incidence of heart failure in the diabetic patient is due to the toxic triad of diabetic cardiomyopathy, left ventricular hypertrophy, and extensive coronary artery disease.ConclusionHigh risk of cardiovascular events, heart failure, and mortality in type 2 diabetes can be lowered with risk factor reduction and therapies that prevent or improve ventricular function. (Endocr Pract. 2008;14:924-932)     

Hematopoietic stem cell transplantation with umbilical cord multipotent stromal cell infusion for the treatment of aplastic anemia—a single-center experience

Background aimsThe purpose of this study was to observe the outcome of co-transfusion of umbilical cord multipotent stromal cells (UC-MSC) and allogeneic hematopoietic stem cells in the treatment of heavily-transfused patients with severe aplastic anemia.MethodsOf the 22 patients, eight cases received haploidentical hematopoietic stem cells from granulocyte colony-stimulating factor–primed bone marrow and peripheral blood grafts; the other patients received granulocyte colony-stimulating factor–mobilized peripheral blood grafts from human leukocyte antigen–matched related (six cases) and unrelated donors (eight cases). MSCs were intravenously infused at a mean dose of 1.2 × 10⁶/ kg (range, 0.27–2.5 × 10⁶/kg). Fludarabine-based conditioning was conducted, and graft-versus-host disease prophylaxis containing cyclosporine A, methotrexate and mycophenolate mofetil with or without addition of anti-CD25 monoclonal antibody was performed. Hematopoietic engraftment, the occurrence of graft-versus-host disease (GVHD) and infections and overall survival were documented.ResultsAll patients had rapid engraftment; mean time for neutrophil and platelet recovery was 13.95 d and 20.27 d, respectively. No acute toxicity associated with UC-MSC transfusion was observed. Acute GVHD developed in seven cases (grade I–II), and none had development of chronic GVHD. Cytomegalovirus reactivation was observed in 11 cases. One patient died of pulmonary complication 6 months after transplantation. Twenty-one patients are currently alive, at a median follow-up of 15 months; they are transfusion-independent and reached full donor chimerism at the time of reporting.ConclusionsUC-MSC infusion might be an alternative option to promote hematopoietic engraftment and reduce the occurrence of GHVD in hematopoietic stem cell transplantation in the treatment of heavily transfused patients with severe aplastic anemia.     

Molecular Description of Familial Defective APOB-100 in Malaysia

Familial ligand-defective apolipoprotein B-100 is characterized by elevated plasma low-density lipoprotein levels and premature heart disease. This study aims to determine apolipoprotein B gene mutations among Malaysians with clinical diagnoses of familial hypercholesterolemia and to compare the phenotype of patients with apolipoprotein B gene mutations to those with a low-density lipoprotein receptor gene mutation. A group of 164 patients with a clinical diagnosis of familial hypercholesterolemia was analyzed. Amplicons in exon 26 and exon 29 of the apolipoprotein B gene were screened for genetic variants using denaturing gradient high-performance liquid chromatography; 10 variants were identified. Five novel mutations were detected (p.Gln2485Arg, p.Thr3526Ala, p.Glu3666Lys, p.Tyr4343CysfsX221, and p.Arg4297His). Those with familial defective apolipoprotein had a less severe phenotype than those with familial hypercholesterolemia. An apolipoprotein gene defect is present among Malaysian familial hypercholesterolemics. Those with both mutations show a more severe phenotype than those with one gene defect.