Risk factors for renal allograft loss in patients with systemic lupus erythematosus

Risk factors for renal allograft loss in patients with systemic lupus erythematosus. Controversy exists regarding the risk factors for renal allograft loss in patients with systemic lupus erythematosus (SLE). This study is a retrospective evaluation of each of these independent risk factors in 80 renal transplants for ESRD secondary to SLE done at our institution between 1971 and 1994. Our entire non-diabetic cohort of 1,966 renal transplants is used as a comparison group. Our results showed equivalent graft survival rates between lupus patients and the cohort at 1, 5 and 10 years (P = 0.56). However, an analysis of cyclosporine-era cadaver grafts revealed that the lupus group had poorer 5-year graft survival than the cohort (41% vs. 71%, P = 0.02). Evaluation of cyclosporine-era lupus graft survival showed significantly improved out-come in living-related lupus recipients over cadaver grafts at five years (89% vs. 41%, P = 0.003). The majority of grafts lost in the lupus cadaver recipients were due to chronic rejection. Rejection was increased in lupus recipients: 69% of lupus patients experienced rejection in the first year compared to 58% of controls (P = 0.01). Stratified for age, sex, race and cyclosporine use, this difference remained significant (P = 0.003, relative risk 1.7). Nephrectomy, splenectomy and 3 to 6 months of pretransplant dialysis did not improve graft survival. A dialysis duration of greater than 25 months predicted worse graft survival (P = 0.01). Among lupus patients, PRA did not correlate with graft outcome (P = 0.5), and HLA-identical cadaver grafts had improved outcomes compared to cadaver grafts. We conclude that acute and chronic rejection are the major risk factors for graft loss in lupus patients. The superior outcome of living-related over cadaver grafts in lupus patients suggests an increased role for living-related grafts. Pretransplant dialysis, nephrectomy and splenectomy are not indicated

Stability of the human faecal microbiome in a cohort of adult men

Characterizing the stability of the gut microbiome is important to exploit it as a therapeutic target and diagnostic biomarker. We metagenomically and metatranscriptomically sequenced the faecal microbiomes of 308 participants in the Health Professionals Follow-Up Study. Participants provided four stool samples—one pair collected 24–72 h apart and a second pair ~6 months later. Within-person taxonomic and functional variation was consistently lower than between-person variation over time. In contrast, metatranscriptomic profiles were comparably variable within and between subjects due to higher within-subject longitudinal variation. Metagenomic instability accounted for ~74% of corresponding metatranscriptomic instability. The rest was probably attributable to sources such as regulation. Among the pathways that were differentially regulated, most were consistently over- or under-transcribed at each time point. Together, these results suggest that a single measurement of the faecal microbiome can provide long-term information regarding organismal composition and functional potential, but repeated or short-term measures may be necessary for dynamic features identified by metatranscriptomics

IFNβ Protects Neurons from Damage in a Murine Model of HIV-1 Associated Brain Injury.

Infection with human immunodeficiency virus-1 (HIV-1) causes brain injury. Type I interferons (IFNα/β) are critical mediators of any anti-viral immune response and IFNβ has been implicated in the temporary control of lentiviral infection in the brain. Here we show that transgenic mice expressing HIV-1 envelope glycoprotein 120 in their central nervous system (HIVgp120tg) mount a transient IFNβ response and provide evidence that IFNβ confers neuronal protection against HIVgp120 toxicity. In cerebrocortical cell cultures, neuroprotection by IFNβ against gp120 toxicity is dependent on IFNα receptor 1 (IFNAR1) and the β-chemokine CCL4, as IFNAR1 deficiency and neutralizing antibodies against CCL4, respectively, abolish the neuroprotective effects. We find in vivo that IFNβ mRNA is significantly increased in HIVgp120tg brains at 1.5, but not 3 or 6 months of age. However, a four-week intranasal IFNβ treatment of HIVgp120tg mice starting at 3.5 months of age increases expression of CCL4 and concomitantly protects neuronal dendrites and pre-synaptic terminals in cortex and hippocampus from gp120-induced damage. Moreover, in vivo and in vitro data suggests astrocytes are a major source of IFNβ-induced CCL4. Altogether, our results suggest exogenous IFNβ as a neuroprotective factor that has potential to ameliorate in vivo HIVgp120-induced brain injury

Diagnostic performance of tuberculosis-specific IgG antibody profiles in patients with presumptive tuberculosis from two continents

Background. Development of rapid diagnostic tests for tuberculosis is a global priority. A  whole proteome screen identified Mycobacterium tuberculosis antigens associated with serological responses in tuberculosis patients. We used World Health Organization (WHO) target product profile (TPP) criteria for a detection test and triage test to evaluate these antigens. Methods. Consecutive patients presenting to microscopy centers and district hospitals in Peru and to outpatient clinics at a tuberculosis reference center in Vietnam were recruited. We tested blood samples from 755 HIV–uninfected adults with presumptive pulmonary tuberculosis to measure IgG antibody responses to 57 M. tuberculosis antigens using a field-based multiplexed serological assay and a 132-antigen bead-based reference assay. We evaluated single antigen performance and models of all possible 3-antigen combinations and multiantigen combinations. Results. Three-antigen and multiantigen models performed similarly and were superior to single antigens. With specificity set at 90% for a detection test, the best sensitivity of a 3-antigen model was 35% (95% confidence interval [CI], 31–40). With sensitivity set at 85% for a triage test, the specificity of the best 3-antigen model was 34% (95% CI, 29–40). The reference assay also did not meet study targets. Antigen performance differed significantly between the study sites for 7/22 of the best-performing antigens. Conclusions. Although M. tuberculosis antigens were recognized by the IgG response during tuberculosis, no single antigen or multiantigen set performance approached WHO TPP criteria for clinical utility among HIV-uninfected adults with presumed tuberculosis in high-volume, urban settings in tuberculosis-endemic countries

AMPK:a target for drugs and natural products with effects on both diabetes and cancer

The AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy that appears to have arisen at an early stage during eukaryotic evolution. In 2001 it was shown to be activated by metformin, currently the major drug for treatment for type 2 diabetes. Although the known metabolic effects of AMPK activation are consistent with the idea that it mediates some of the therapeutic benefits of metformin, as discussed below it now appears unlikely that AMPK is the sole target of the drug. AMPK is also activated by several natural plant products derived from traditional medicines, and the mechanisms by which they activate AMPK are discussed. One of these is salicylate, probably the oldest medicinal agent known to humankind. The salicylate prodrug salsalate has been shown to improve metabolic parameters in subjects with insulin resistance and prediabetes, and whether this might be mediated in part by AMPK is discussed. Interestingly, there is evidence that both metformin and aspirin provide some protection against development of cancer in humans, and whether AMPK might be involved in these effects is also discussed

Structural insights into TAZ2 domain-mediated CBP/p300 recruitment by transactivation domain 1 of the lymphopoietic transcription factor E2A.

The E-protein transcription factors guide immune cell differentiation, with E12 and E47 (hereafter called E2A) being essential for B-cell specification and maturation. E2A and the oncogenic chimera E2A-PBX1 contain three transactivation domains (ADs), with AD1 and AD2 having redundant, independent, and cooperative functions in a cell-dependent manner. AD1 and AD2 both mediate their functions by binding to the KIX domain of the histone acetyltransferase paralogues CREB-binding protein (CBP) and E1A-binding protein P300 (p300). This interaction is necessary for B-cell maturation and oncogenesis by E2A-PBX1 and occurs through conserved ϕ-x-x-ϕ-ϕ motifs (with ϕ denoting a hydrophobic amino acid) in AD1 and AD2. However, disruption of this interaction via mutation of the KIX domain in CBP/p300 does not completely abrogate binding of E2A and E2APBX1. Here, we determined that E2A-AD1 and E2A-AD2 also interact with the TAZ2 domain of CBP/p300. Characterization of the TAZ2:E2AAD1(1-37) complex indicated that E2A-AD1 adopts an α-helical structure and uses its ϕ-x-x-ϕ-ϕ motif to bind TAZ2. While this region overlapped with the KIX recognition region, key KIX-interacting E2A-AD1 residues were exposed, suggesting that E2A-AD1 could simultaneously bind both the KIX and TAZ2 domains. However, we did not detect a ternary complex involving E2A-AD1, KIX, and TAZ2 and found that E2A containing both intact AD1 and AD2 is required to bind to CBP/p300. Our findings highlight the structural plasticity and promiscuity of E2A-AD1 and suggest that E2A binds both the TAZ2 and KIX domains of CBP/p300 through AD1 and AD2

Comparison between clinical significance of serum proinflammatory proteins (IL-6 and CRP) and classic tumor markers (CEA and CA 19-9) in gastric cancer

Gastric cancer (GC) is a second most common cause of cancer-related death and represents an inflammation-driven malignancy. It has been suggested that interleukin 6 (IL-6) and C-reactive protein (CRP) play a potential role in the growth and progression of GC. The aim of the present study was to compare clinical significance of IL-6 and CRP with classic tumor markers—carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) in GC patients. The study included 92 patients with GC and 70 healthy subjects. The serum concentrations of IL-6, CEA and CA 19-9 were determined using immunoenzyme assays, whereas CRP using immunoturbidimetric method. We defined the diagnostic criteria and prognostic value for proteins tested. In GC patients, the serum concentrations of all the proteins tested were significantly higher than in healthy subjects. The IL-6, CEA and CA 19-9 levels correlated with nodal metastases, while CRP with tumor stage, gastric wall invasion, presence of nodal and distant metastases. Diagnostic sensitivity of IL-6 was higher (85%) than those of other markers (CRP 66%, CA 19-9 34%, CEA 22%) and increased in combined use with CRP or CEA (88%). The area under ROC curve for IL-6 was larger than those of CRP and classic tumor markers (CEA and CA 19-9). None of the proteins tested was independent prognostic factor for the survival of GC patients. Our findings indicate better usefulness of serum proinflammatory proteins—IL-6 and CRP than classic tumor markers—CEA and CA 19-9 in the diagnosis of GC

Possible association between a genetic polymorphism at 8q24 and risk of upper gastrointestinal cancer

Over recent years, genome wide association studies (GWAS) have contributed to our understanding of genetic susceptibility to sporadic cancer. In this study, we assessed the association between upper gastrointestinal cancer risk and four GWAS-identified single nucleotide polymorphisms (SNPs), previously implicated in prostate and colorectal cancer susceptibility. Genotyping for each SNP was performed in two, independent, Caucasian, population-based case-control studies. The first study comprised 290 gastric cancer cases and 374 controls. The second study included 185 non-cardia gastric cancers, 123 cardia cancers, 158 oesophageal cancers, and 209 controls. Odds ratios were computed from logistic models and adjusted for potential confounding variables. An inverse association was observed between the SNP rs1447295, located at 8q24, and gastric cancer risk in the first study population (odds ratio [OR] = 0.63; 95% Confidence Interval [CI], 0.41–0.97). A positive association was observed for the same SNP and oesophageal squamous cell carcinoma in the second study population (OR = 7.43; 95% CI, 1.37–49.98). No significant associations were detected in either study for the three remaining SNPs (rs6983297, rs10505477 and rs719725). Our data represent novel findings on heritable susceptibility to gastric and oesophageal cancer and warrant validation in additional populations