Elevated interleukin-10: a new cause of dyslipidemia leading to severe HDL deficiency.

BACKGROUND: Low high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. Investigating mechanisms underlying acquired severe HDL deficiency in noncritically ill patients ("disappearing HDL syndrome") could provide new insights into HDL metabolism. OBJECTIVE: To determine the cause of low HDL-C in patients with severe acquired HDL deficiency. METHODS AND RESULTS: Patients with intravascular large B-cell lymphoma (n = 2), diffuse large B-cell lymphoma (n = 1), and autoimmune lymphoproliferative syndrome (n = 1) presenting with markedly decreased HDL-C, low low-density lipoprotein cholesterol (LDL-C), and elevated triglycerides were identified. The abnormal lipoprotein profile returned to normal after therapy in all 4 patients. All patients were found to have markedly elevated serum interleukin-10 (IL-10) levels that also normalized after therapy. In a cohort of autoimmune lymphoproliferative syndrome patients (n = 93), IL-10 showed a strong inverse correlation with HDL-C (R(2) = 0.3720, P < .0001). A direct causal role for increased serum IL-10 in inducing the observed changes in lipoproteins was established in a randomized, placebo-controlled clinical trial of recombinant human IL-10 in psoriatic arthritis patients (n = 18). Within a week of initiating subcutaneous recombinant human IL-10 injections, HDL-C precipitously decreased to near-undetectable levels. LDL-C also decreased by more than 50% (P < .0001) and triglycerides increased by approximately 2-fold (P < .005). All values returned to baseline after discontinuing IL-10 therapy. CONCLUSION: Increased IL-10 causes severe HDL-C deficiency, low LDL-C, and elevated triglycerides. IL-10 is thus a potent modulator of lipoprotein levels, a potential new biomarker for B-cell disorders, and a novel cause of disappearing HDL syndrome.

Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis.

Genetic polymorphisms in the interleukin-2 receptor α (IL-2Rα) chain (CD25) locus are associated with several human autoimmune diseases, including multiple sclerosis (MS). Blockade of CD25 by the humanized monoclonal antibody daclizumab decreases MS-associated inflammation but has surprisingly limited direct inhibitory effects on activated T cells. The present study describes unexpected effects of daclizumab therapy on innate lymphoid cells (ILCs). The number of circulating retinoic acid receptor-related orphan receptor γt-positive ILCs, which include lymphoid tissue inducer (LTi) cells, was found to be elevated in untreated MS patients compared to healthy subjects. Daclizumab therapy not only decreased numbers of ILCs but also modified their phenotype away from LTi cells and toward a natural killer (NK) cell lineage. Mechanistic studies indicated that daclizumab inhibited differentiation of LTi cells from CD34⁺ hematopoietic progenitor cells or c-kit⁺ ILCs indirectly, steering their differentiation toward immunoregulatory CD56(bright) NK cells through enhanced intermediate-affinity IL-2 signaling. Because adult LTi cells may retain lymphoid tissue-inducing capacity or stimulate adaptive immune responses, we indirectly measured intrathecal inflammation in daclizumab-treated MS patients by quantifying the cerebrospinal fluid chemokine (C-X-C motif) ligand 13 and immunoglobulin G index. Both of these inflammatory biomarkers were inhibited by daclizumab treatment. Our study indicates that ILCs are involved in the regulation of adaptive immune responses, and their role in human autoimmunity should be investigated further, including their potential as therapeutic targets.

Do premenopausal women with major depression have low bone mineral density? A 36-month prospective study.

BACKGROUND: An inverse relationship between major depressive disorder (MDD) and bone mineral density (BMD) has been suggested, but prospective evaluation in premenopausal women is lacking. METHODS: Participants of this prospective study were 21 to 45 year-old premenopausal women with MDD (n = 92) and healthy controls (n = 44). We measured BMD at the anteroposterior lumbar spine, femoral neck, total hip, mid-distal radius, trochanter, and Ward's triangle, as well as serum intact parathyroid hormone (iPTH), ionized calcium, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-hour urinary-free cortisol levels at 0, 6, 12, 24, and 36 months. 25-hydroxyvitamin D was measured at baseline. RESULTS: At baseline, BMD tended to be lower in women with MDD compared to controls and BMD remained stable over time in both groups. At baseline, 6, 12, and 24 months intact PTH levels were significantly higher in women with MDD vs. controls. At baseline, ionized calcium and 25-hydroxyvitamin D levels were significantly lower in women with MDD compared to controls. At baseline and 12 months, bone-specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD vs. controls. Plasma ACTH was also higher in women with MDD at baseline and 6 months. Serum osteocalcin, urinary N-telopeptide, serum cortisol, and urinary free cortisol levels were not different between the two groups throughout the study. CONCLUSION: Women with MDD tended to have lower BMD than controls over time. Larger and longer studies are necessary to extend these observations with the possibility of prophylactic therapy for osteoporosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00006180.

Unmedicated, remitted patients with major depression have decreased serum immunoglobulin A.

Patents with major depression have evidence of a proinflammatory state with consistent elevations in acute phase proteins and in the levels of inflammatory mediators such as interleukin-6 and tumor necrosis factor-α. We report here a study of the serum levels of immunoglobulin A (IgA) in medication-free patients with major depression in the remitted state (ruMDD). Selective IgA deficiency is the most common form of immunoglobulin abnormality, and is often associated with a higher than expected incidence of proinflammatory and autoimmune phenomena. We measured serum IgG, IgM, and IgA in 28 ruMDD patients and 27 healthy subjects (Ctrl) at 0 (pretreatment), 7, and 24h following sham depletion and tryptophan (TrpD) depletion conducted at least 8 days apart under balanced, randomized, blinded conditions. Immunoglobulins were measured by automated immunonephelometry. Data were analyzed by repeated measures ANOVA with diagnosis as a fixed effect and drug (TrpD vs. sham), and time as repeated measures factors. Serum IgA was consistently lower in ruMDD patients vs. Ctrl at all time points examined (p<0.04 for main effect of diagnosis). Serum IgG and IgM levels did not show significant differences by diagnosis. Medication-free patients with major depression in the remitted state have a significant reduction in serum IgA levels measured on multiple occasions. In the light of the fact that IgA serves many immunomodulatory, anti-inflammatory roles, this finding supports the concept that major depressive illness represents a proinflammatory state.

Hypermutation of ApoB mRNA by rat APOBEC-1 overexpression mimics APOBEC-3 hypermutation.

APOBEC-3 proteins induce C-to-U hypermutations in the viral genome of various viruses and have broad antiviral activity. Generally, only a small proportion of viral genomes (<10(-)(2)) are hypermutated by APOBEC-3s, but often many cytidines (up to 40%) are converted into uridine. The mechanism of this unique selective hypermutation remains unknown. We found that rat APOBEC-1 overexpression had a hypermutation pattern similar to that of APOBEC-3s on its substrate apolipoprotein B (apoB) mRNA. Transient plasmid transfection of rat APOBEC-1 resulted in 0.4% and 1.8% hypermutations with apoB mRNA in HepG2 and McA7777 cells, respectively. The low frequency of hypermutated apoB mRNA targets was enriched by differential DNA denaturation PCR at 72-76 °C, with hypermutation levels increasing up to 67%. Up to 69.6% of cytidines in HepG2 and up to 75.5% of cytidines in McA7777 cells were converted into uridines in the hypermutated apoB mRNA. When rat APOBEC-1 was overexpressed by adenovirus, the hypermutation frequency of apoB mRNA increased from 0.4% to ∼20% and was readily detected by regular PCR. However, this higher expression efficiency only increased the frequency of hypermutation, not the number of affected cytidines in hypermutated targets. Rat APOBEC-1 hypermutation was modulated by cofactors and eliminated by an E181Q mutation, indicating the role of cofactors in hypermutation. The finding of an APOBEC-3 hypermutation pattern with rat APOBEC-1 suggests that cofactors could also be involved in APOBEC-3 hypermutation. Using hepatitis B virus hypermutation, we found that KSRP increased APOBEC-3C and APOBEC-3B hypermutation. These data show that, like rat APOBEC-1 hypermutation, cellular factors may play a regulatory role in APOBEC-3 hypermutation.

Human apolipoprotein E genotypes differentially modify house dust mite-induced airway disease in mice.

Apolipoprotein E (apoE) is an endogenous negative regulator of airway hyperreactivity (AHR) and mucous cell metaplasia in experimental models of house dust mite (HDM)-induced airway disease. The gene encoding human apoE is polymorphic, with three common alleles (ε2, ε3, and ε4) reflecting single amino acid substitutions at amino acids 112 and 158. The objective of this study was to assess whether the human apoE alleles modify airway responses to repeated nasal HDM challenges. Mice expressing the human apoE ε2 (huApoE2), ε3 (huApoE3), or ε4 (huApoE4) alleles received nasal HDM challenges, and airway responses were compared with mice expressing the endogenous murine apoE gene (muApoE). huApoE3 mice displayed significant reductions in AHR, mucous cell metaplasia, and airway inflammation compared with muApoE mice. The attenuated severity of airway inflammation in huApoE3 mice was associated with reductions in lung mRNA levels of Th2 and Th17 cytokines, as well as chemokines (CCL7, CCL11, CCL24). huApoE4 mice had an intermediate phenotype, with attenuated AHR and IgE production, compared with muApoE mice, whereas airway inflammation and mucous cell metaplasia were not reduced. In contrast, HDM-induced airway responses were not modified in mice expressing the huApoE2 allele. We conclude that the polymorphic huApoE alleles differentially modulate HDM-induced airway disease, which can be stratified, in rank order of increasing disease severity, ε3 < ε4 < ε2. These results raise the possibility that the polymorphic apoE alleles may modify disease severity in human asthma.

Accelerated lymphocyte reconstitution and long-term recovery after transplantation of lentiviral-transduced rhesus CD34+ cells mobilized by G-CSF and plerixafor.

OBJECTIVE: Granulocyte colony-stimulating factor (G-CSF) in combination with plerixafor produces significant mobilization of CD34(+) cells in rhesus macaques. We sought to evaluate whether these CD34(+) cells can stably reconstitute blood cells with lentiviral gene marking. MATERIALS AND METHODS: We performed hematopoietic stem cell transplantation using G-CSF and plerixafor-mobilized rhesus CD34(+) cells transduced with a lentiviral vector, and these data were compared with those of G-CSF and stem cell factor mobilization. RESULTS: G-CSF and plerixafor mobilization resulted in CD34(+) cell yields that were twofold higher than yields with G-CSF and stem cell factor. CD123 (interleukin-3 receptor) expression was greater in G-CSF and plerixafor-mobilized CD34(+) cells when compared to G-CSF alone. Animals transplanted with G-CSF and plerixafor-mobilized cells showed engraftment of all lineages, similar to animals who received G-CSF and stem cell factor-mobilized grafts. Lymphocyte engraftment was accelerated in animals receiving the G-CSF and plerixafor-mobilized CD34(+) cells. One animal in the G-CSF and plerixafor group developed cold agglutinin-associated skin rash during the first 3 months of rapid lymphocyte recovery. One year after transplantation, all animals had 2% to 10% transgene expression in all blood cell lineages. CONCLUSIONS: G-CSF and plerixafor-mobilized CD34(+) cells accelerate lymphocyte engraftment and contain hematopoietic stem cell capable of reconstituting multilineage blood cells. These findings indicate important differences to consider in plerixafor-based hematopoietic stem cell mobilization protocols in rhesus macaques.

Assessment of ovarian function after preparative chemotherapy and total body radiation for adoptive cell therapy.

The aim of the study is to analyze treatment-induced gonadal damage and premature ovarian failure after adoptive cell therapy (ACT) after a cytotoxic lymphodepleting preparative regimen. Records of 66 consecutive females who received ACT at the Surgery Branch, National Cancer Institute, NIH (Bethesda, MD) were reviewed. Patients received a conditioning regimen of high-dose cyclophosphamide (60 mg/kg x 2 doses) and fludarabine (25 mg/m² x 5 doses). Some patients also received total body radiation at 200 or 600 cGy. Assessment of ovarian function was determined by analysis of monthly follicle stimulating hormone (FSH) levels, menstrual history, and symptoms. Among patients with serum available and normal pretreatment ovarian function, 21 had a preparative regimen with chemotherapy alone and 5 patients had received chemotherapy with total body radiation. Nine (43%) patients in the chemotherapy cohort and all 5 patients in the chemotherapy plus total body radiation cohort had persistently elevated FSH levels and were given the diagnosis of premature ovarian failure. Twelve (57%) patients had normal FSH levels at 6 months posttreatment. Median age of all patients at treatment was 34 years. Median age of women retaining normal ovarian function was 30 (range, 19-45) vs. 41 years (range, 30-49) for those who did not regain function. The conditioning regimen of 2 doses of cyclophosphamide (60 mg/kg) and 5 doses of fludarabine (25 mg/m²) may induce gonadal damage and premature ovarian failure. Younger age at treatment was associated with a higher frequency of normal ovarian function posttreatment, whereas adding total body radiation was associated with a high risk of ovarian failure.

The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients.

CONTEXT: The substitution of liothyronine (L-T3) for levothyroxine (L-T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L-T3 for L-T4 therapeutic substitution. Objective To characterize the pharmcodynamic equivalence of L-T3 and L-T4. DESIGN: Randomized, double-blind, cross-over intervention study. SETTING: NIH clinical center. PATIENTS: Ten thyroidectomized patients. INTERVENTIONS: Study participants were treated with L-T3 or L-T4 with a target TSH >or= 0.5

Hypermutation induced by APOBEC-1 overexpression can be eliminated.

APOBEC-1 overexpression in liver has been shown to effectively reduce apoB-100 levels. However, nonspecific hypermutation and liver tumor formation potentially related to hypermutation in transgenic animals compromise its potential use for gene therapy. In studying apoB mRNA editing regulation, we found that the core editing auxiliary factor ACF dose-dependently increases APOBEC-1 nonspecific hypermutation and specific editing with variable site sensitivity. Overexpression of APOBEC-1 together with ACF in human hepatic HepG2 cells hypermutated apoB mRNAs 20%-65% at sites 6639, 6648, 6655, 6762, 6802, and 6845, in addition to the normal 90% editing at 6666. The hypermutation activity of APOBEC-1 was decreased to background levels by a single point APOBEC-1 mutation of P29F or E181Q, while 50% of wild-type control editing at the normal site was retained. The hypermutations on both apoB and novel APOBEC-1 target 1 (NAT1) mRNA were also decreased to background levels with P29F and E181Q mutants in rat liver primary culture cells. The loss of hypermutation with the mutants was associated with significantly decreased APOBEC-1/ACF interaction. These data suggest that nonspecific hypermutation induced by overexpressing APOBEC-1 can be virtually eliminated by site-specific mutation, while maintaining specific editing activity at the normal site, reopening the potential use of APOBEC-1 gene therapy for hyperlipidemia.

CD36 is a novel serum amyloid A (SAA) receptor mediating SAA binding and SAA-induced signaling in human and rodent cells.

Serum amyloid A (SAA) is a major acute phase protein involved in multiple physiological and pathological processes. This study provides experimental evidence that CD36, a phagocyte class B scavenger receptor, functions as a novel SAA receptor mediating SAA proinflammatory activity. The uptake of Alexa Fluor 488 SAA as well as of other well established CD36 ligands was increased 5-10-fold in HeLa cells stably transfected with CD36 when compared with mock-transfected cells. Unlike other apolipoproteins that bind to CD36, only SAA induced a 10-50-fold increase of interleukin-8 secretion in CD36-overexpressing HEK293 cells when compared with control cells. SAA-mediated effects were thermolabile, inhibitable by anti-SAA antibody, and also neutralized by association with high density lipoprotein but not by association with bovine serum albumin. SAA-induced cell activation was inhibited by a CD36 peptide based on the CD36 hexarelin-binding site but not by a peptide based on the thrombospondin-1-binding site. A pronounced reduction (up to 60-75%) of SAA-induced pro-inflammatory cytokine secretion was observed in cd36(-/-) rat macrophages and Kupffer cells when compared with wild type rat cells. The results of the MAPK phosphorylation assay as well as of the studies with NF-kappaB and MAPK inhibitors revealed that two MAPKs, JNK and to a lesser extent ERK1/2, primarily contribute to elevated cytokine production in CD36-overexpressing HEK293 cells. In macrophages, four signaling pathways involving NF-kappaB and three MAPKs all appeared to contribute to SAA-induced cytokine release. These observations indicate that CD36 is a receptor mediating SAA binding and SAA-induced pro-inflammatory cytokine secretion predominantly through JNK- and ERK1/2-mediated signaling.

Targeted antagonism of CXCR4 mobilizes progenitor cells under investigation for cardiovascular disease.

BACKGROUND AIMS: Bone marrow (BM)-derived cells may repair cardiovascular injury but populations of interest circulate in small numbers. Cytokines such as granulocyte-colony-stimulating factor mobilize cells under investigation for this purpose, including CD133+ but require injections over multiple days and may promote inflammation. The purpose of this study was to evaluate the effects of a novel CXCR4 inhibitor (plerixafor), previously shown to mobilize CD34+ stem cells, on CD133+ mobilization and markers of inflammation. METHODS: Healthy subjects received a single subcutaneous injection of plerixafor in escalating doses: 240 mcg/kg (n = 3), 320 mcg/kg (n = 5) and 400 mcg/kg (n = 7). CD133+ and CD133+/VEGFR-2+ cells were measured by flow cytometry at baseline, then 4-6 h following plerixafor injection. Markers of inflammation in serum were measured at baseline, then again 10 h following injection of the 400 mcg/kg dose. RESULTS: Across all doses, white blood cells increased on average three-fold from baseline values. CD133+ cells increased on average 24-fold (from 616 +/- 141 cells/mL to 14 713 +/- 4423 cells/mL, P = 0.0064) without clear evidence of a dose effect. CD133+/VEGFR-2+ cells ranged from 0 to 20 cells/mL at baseline and from 0 to 124 cells/mL following plerixafor administration, although the rarity of these cells precluded a statistical analysis of this population. C-reactive protein and serum amyloid type A were not increased after the 400 mcg/kg dose. Pro-inflammatory cytokine levels were undetectable before and after plerixafor, except for macrophage inflammatory protein-1 beta, which increased slightly but significantly after the 400 mcg/kg dose of plerixafor (P = 0.0156). CONCLUSIONS: CD133+ cells are mobilized into the circulation following a single injection of the CXCR4 antagonist plerixafor, without clear evidence for systemic activation of inflammation. This effect may be of importance in cell-based approaches for treating cardiovascular diseases.

Variability of C-reactive protein levels among patients with stable coronary artery disease and on statin therapy.

BACKGROUND: High sensitivity C-reactive protein, a marker of inflammation, has been proposed to stratify coronary artery disease risk and is lowered by HMG-CoA reductase (statin) therapy. However, the reproducibility of persistently elevated hs-CRP levels and association with other markers of inflammation in patients with stable CAD on aggressive statin therapy is unknown. OBJECTIVES: To determine the reproducibility of hs-CRP levels measured within 2 weeks in patients with documented CAD with stable symptoms and to identify associations with other markers of inflammation. METHODS: Levels of hs-CRP were measured twice within 14 days (7 +/- 4) in 23 patients (22 males and 1 female, average age 66 +/- 10 years) with stable CAD and hs-CRP > or = 2.0 mg/L but < or = 10 mg/L at visit 1. All patients had received statins for cholesterol management (low density lipoprotein-cholesterol 84 +/- 25 mg/dl) with no dose change for > 3 months. None had a history or evidence of malignancy, chronic infection or inflammation, or recent trauma. There was no change in medications between visits 1 and 2, and no patient reported a change in symptoms or general health during this interval. White blood cell count and pro- and anti-inflammatory cytokines were measured at both visits. RESULTS: hs-CRP levels tended to be lower at visit 2 (median 2.4 mg/L, range 0.8-11 mg/L) than at visit 1 (median 3.3 mg/L, range 2.0-9.7; P = 0.1793). However, between the two visits hs-CRP levels decreased by more than 1.0 mg/L in 10 patients and increased by more than 1.0 mg/L in 4 patients. Changes in hs-CRP levels were unrelated to changes in levels of white blood cells (P = 0.4353). Of the cytokines tested, only the antiinflammatory cytokine interleukin-1 receptor antagonist and the pro-inflammatory cytokine interleukin-8 were above lower limits of detection, but there were no correlations between changes in these values and changes in hs-CRP (both P > 0.5). CONCLUSIONS: In stable CAD patients on aggressive statin therapy, hs-CRP levels may fluctuate over brief periods in the absence of changes in health, cardiac symptom status and medications, and without corroboration with other measures of inflammation. Accordingly, elevated hs-CRP levels should be interpreted with caution in this setting.

Role of human CD36 in bacterial recognition, phagocytosis, and pathogen-induced JNK-mediated signaling.

Scavenger receptor CD36 mediates Staphylococcus aureus phagocytosis and initiates TLR2/6 signaling. We analyzed the role of CD36 in the uptake and TLR-independent signaling of various bacterium, including Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, S. aureus, and Enterococcus faecalis. Expression of human CD36 in HeLa cells increased the uptake of both gram-positive and gram-negative bacteria compared with the control mock-transfected cells. Bacterial adhesion was associated with pathogen phagocytosis. Upon CD36 transfection, HEK293 cells, which demonstrate no TLR2/4 expression, acquired LPS responsiveness as assessed by IL-8 production. The cells demonstrated a marked 5- to 15-fold increase in cytokine release upon exposure to gram-negative bacteria, while the increase was much smaller (1.5- to 3-fold) with gram-positive bacteria and lipoteichoic acid. CD36 down-regulation utilizing CD36 small interfering RNA reduced cytokine release by 40-50% in human fibroblasts induced by both gram-negative and gram-positive bacteria as well as LPS. Of all MAPK signaling cascade inhibitors tested, only the inhibitor of JNK, a stress-activated protein kinase, potently blocked E. coli/LPS-stimulated cytokine production. NF-kappaB inhibitors were ineffective, indicating direct TLR-independent signaling. JNK activation was confirmed by Western blot analyses of phosphorylated JKN1/2 products. Synthetic amphipathic peptides with an alpha-helical motif were shown to be efficient inhibitors of E. coli- and LPS-induced IL-8 secretion as well as JNK1/2 activation/phosphorylation in CD36-overexpressing cells. These results indicate that CD36 functions as a phagocytic receptor for a variety of bacteria and mediates signaling induced by gram-negative bacteria and LPS via a JNK-mediated signaling pathway in a TLR2/4-independent manner.

Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy.

BACKGROUND: Lamivudine is increasingly being used to prevent hepatitis B reactivation in patients with cancer who test positive for hepatitis B surface antigen (HBsAg) and are undergoing chemotherapy. PURPOSE: To determine whether preventive lamivudine reduces chemotherapy-induced hepatitis B virus (HBV)-related morbidity and mortality in patients with cancer who test positive for HBsAg. DATA SOURCES: MEDLINE, Ovid MEDLINE, TOXNET, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched in all languages until June 2007. STUDY SELECTION: Clinical trials and cohort studies that reported the efficacy of preventive lamivudine versus control on HBV reactivation in patients who tested positive for HBsAg and were receiving chemotherapy were included. Additional requirements included minimum sample size (>5 participants per treatment group) and reported HBV-related morbidity and mortality data. DATA EXTRACTION: Two investigators independently did literature searches and data extraction, and 2 other investigators independently confirmed study eligibility and data retrieval. DATA SYNTHESIS: Fourteen studies (2 randomized, controlled trials; 8 prospective cohort studies; and 4 retrospective cohort studies) met the predefined criteria for analysis. There were 275 patients in the preventive lamivudine group and 475 control participants for the primary end point of HBV reactivation. With preventive lamivudine, the relative risk for both HBV reactivation and HBV-related hepatitis ranged from 0.00 to 0.21. None of the patients in the preventive lamivudine group developed HBV-related hepatic failure (0 of 108 patients vs. 21 of 162 patients), and only 4 deaths were attributable to HBV (4 of 208 patients vs. 27 of 394 patients) in the preventive lamivudine group. Lamivudine was well tolerated, and no adverse effects were noted. LIMITATIONS: The studies included in the meta-analysis did not consistently report all of the outcomes of interest. Sample sizes were small and only 2 studies had a randomized, controlled design. CONCLUSION: Preventive therapy with lamivudine for patients who test positive for HBsAg and are undergoing chemotherapy may reduce the risk for HBV reactivation and HBV-associated morbidity and mortality.

Protein electrophoresis, immunoelectrophoresis and immunofixation electrophoresis as predictors for high-risk phenotype in familial Waldenström macroglobulinemia.

Protein electrophoresis is used for the detection, evaluation and follow-up of monoclonal gammopathy (MG) conditions such as Waldenström macroglobulinemia (WM). Immunofixation electrophoresis (IFE) is currently the most common method for isotyping of monoclonal gammopathy because of its superior sensitivity relative to immunoelectrophoresis (IEP). We designed a study to evaluate the clinicobiological relevance of small monoclonal bands detected by serum protein electrophoresis, IEP, and IFE. Serum protein electrophoresis, IEP, and IFE were used to evaluate possible monoclonal gammopathy in 46 members (29 relatives and 17 nonbloodline spouses) from 3 families with multiple cases of WM. IFE identified small monoclonal bands initially missed by IEP in 5 individuals (2 blood relatives, 3 spouses) among 46 study participants. All bands were IgM type. Twenty-three individuals, including the 2 blood relatives and 2 of 3 spouses with monoclonal gammopathy, were then followed for a median of 17 years (range, 13-25). The monoclonal gammopathy progressed in the 2 relatives but disappeared in the spouses, and new IgM MG developed in 2 additional relatives with a prior history of IgM polyclonal gammopathy. Small monoclonal bands detected by IFE in a familial context may be biologically meaningful, both as phenotypic biomarkers and possibly as predictors of high risk for WM. Polyclonal IgM may also be a marker of genetic susceptibility in WM families. Larger studies are needed to confirm these observations.

Serum proteins and paraproteins in women with silicone implants and connective tissue disease: a case-control study.

Prior studies have suggested abnormalities of serum proteins, including paraproteins, in women with silicone implants but did not control for the presence of connective-tissue disease (CTD). This retrospective case-control study, performed in tertiary-care academic centers, assessed possible alterations of serum proteins, including paraproteins, in such a population. Seventy-four women with silicone implants who subsequently developed CTD, and 74 age-matched and CTD-matched women without silicone implants, were assessed in the primary study; other groups were used for additional comparisons. Routine serum protein determinations and high-sensitivity protein electrophoresis and immunofixation electrophoresis were performed for detection of paraproteins. Women with silicone implants, either with or without CTD, had significantly lower serum total protein and alpha1-globulin, alpha2-globulin, beta-globulin, gamma-globulin, and IgG levels compared with those without silicone implants. There was no significant difference, however, in the frequency of paraproteinemia between women with silicone implants and CTD (9.5%) and age-matched and CTD-matched women without silicone implants (5.4%) (odds ratio, 1.82; 95% confidence interval, 0.51-6.45). Paraprotein isotypes were similar in the two groups, and the clinical characteristics of the 13 women with paraproteinemia were comparable with an independent population of 10 women with silicone breast implants, CTD, and previously diagnosed monoclonal gammopathies. In summary, this first comprehensive study of serum proteins in women with silicone implants and CTD found no substantially increased risk of monoclonal gammopathy. Women with silicone implants, however, had unexpectedly low serum globulin and immunoglobulin levels, with or without the subsequent development of CTD. The causes and clinical implications of these findings require further investigation.

Long-term evaluation of three multiple-case Waldenstrom macroglobulinemia families.

PURPOSE: Because the clinical significance of immunoglobulin abnormalities reported in relatives of familial Waldenström macroglobulinemia (WM) patients is unknown, we initiated a follow-up study of three WM families originally evaluated 27 years previously. EXPERIMENTAL DESIGN: Of 29 eligible first-degree relatives of WM patients, 27 (93%) had originally participated in clinical and electrophoretic evaluations. We re-contacted all participants for prospective follow-up electrophoretic analysis and other studies. RESULTS: Initially, five relatives had IgM monoclonal gammopathy (IgM MG), and four had IgM polyclonal gammopathy (PG). Twenty-two relatives (81%) were re-evaluated. Median follow-up was 17 years (range, 7-27). At re-contact, all IgM MG persisted or progressed, including three that evolved to WM. Among the four with PG, two new IgM MG cases developed. Overall, seven relatives (26%) had IgM MG, and five (18%) had IgM PG. CONCLUSIONS: Although based on small numbers, this study provides the longest comprehensive follow-up of WM families to date. IgM MG seems to be a phenotypic marker of WM susceptibility in some families and may have a high risk of progression to WM. IgM PG may also be important in WM families. These observations require validation in larger studies and, if confirmed, may be used to identify a cohort (relatives with IgM MG) for future prevention strategies.

Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock.

OBJECTIVE: L-arginine supplementation in sepsis is controversial. Septic shock has been alternatively viewed as an L-arginine-deficient state or as a syndrome caused by excess nitric oxide, an end-product of L-arginine metabolism. DESIGN: Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists). SETTING: Laboratory. SUBJECTS: Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles. INTERVENTIONS: The effects of parenteral L-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis. Two doses were studied that delivered approximately 1.5-fold (10 mg x kg(-1) x hr(-1)) and 15-fold (100 mg x kg(-1) x hr(-1)) the L-arginine dose typically administered with standard total parenteral nutrition. Animals in the low- and high-dose L-arginine arms were further randomized to receive vehicle alone or N-acetylcysteine (20 mg x kg(-1) x hr(-1)) as an antioxidant to prevent peroxynitrite formation. MEASUREMENTS AND MAIN RESULTS: The main measurements were hemodynamics, plasma arginine and ornithine, serum nitrate/nitrite, laboratory studies for organ injury, and survival. Both doses of L-arginine similarly increased mortality (p = .02), and worsened shock (p = .001 for reduced mean arterial pressure). These effects were associated with significant increases in plasma arginine (p = .0013) and ornithine (p = .0021). In addition, serum nitrate/nitrite (p = .02), liver enzymes (p = .08), and blood urea nitrogen/creatinine ratios (p = .001) rose, whereas arterial pH (p = .001) and bicarbonate levels (p = .001) fell. N-acetylcysteine did not significantly decrease any of the harmful effects of L-arginine. Thus, parenteral L-arginine monotherapy was markedly harmful in animals with septic shock. CONCLUSIONS: These findings suggest that supplemental parenteral L-arginine, at doses above standard dietary practices, should be avoided in critically ill patients with septic shock.