As a resident of early endosomal phagosomes, Mycobacterium tuberculosis is connected to the iron uptake system of the host macrophage. β-2-microglobulin (β2m) knockout (KO) mice are more susceptible to tuberculosis than wild-type mice, which is generally taken as a proof for the role of major histocompatibility complex class I (MHC-I)–restricted CD8 T cells in protection against M. tuberculosis. However, β2m associates with a number of MHC-I–like proteins, including HFE. This protein regulates transferrin receptor mediated iron uptake and mutations in its gene cause hereditary iron overload (hemochromatosis). Accordingly, β2m-deficient mice suffer from tissue iron overload. Here, we show that modulating the extracellular iron pool in β2m–KO mice by lactoferrin treatment significantly reduces the burden of M. tuberculosis to numbers comparable to those observed in MHC class I–KO mice. In parallel, the generation of nitric oxide impaired in β2m–KO mice was rescued. Conversely, iron overload in the immunocompetent host exacerbated disease. Consistent with this, iron deprivation in infected resting macrophages was detrimental for intracellular mycobacteria. Our data establish: (a) defective iron metabolism explains the increased susceptibility of β2m-KO mice over MHC-I–KO mice, and (b) iron overload represents an exacerbating cofactor for tuberculosis.

Background: Because of the limitations of serum creatinine as a marker of glomerular filtration rate (GFR) in children, we assessed the diagnostic accuracy of the novel marker β-trace protein (BTP) in comparison with cystatin C (Cys-C), β2-microglobulin (β2-MG), and creatinine as conventional indicators of reduced GFR. Methods: We obtained serum samples from 225 children (age range, 0.2–18 years) with various renal pathologies who were referred for nuclear medicine clearance investigations (technetium-diethylenetriamine pentaacetic acid or chromium-EDTA). We measured Cys-C, BTP (nephelometric tests; Dade Behring), β2-MG (Tinaquant; Roche), and creatinine (enzymatic assay; Creatinine-PAP; Roche). Results: Seventy-five children had reduced GFR (<90 mL · min−1 · 1.73 m−2). One hundred fifty children (independent of gender and age) with values >90 mL · min−1 · 1.73 m−2 comprised the control group with gaussian distributions of BTP and Cys-C concentrations. The upper reference limits (97.5 percentile) were 1.01 mg/L for BTP and 1.20 mg/L for Cys-C. The correlations of nuclear medicine clearance with the reciprocals of BTP, Cys-C, and the Schwartz GFR estimate were significantly higher (r = 0.653, 0.765, and 0.706, respectively; P <0.05) than with the reciprocal of creatinine or β2-MG (r = 0.500 and 0.557, respectively). ROC analysis showed a significantly higher diagnostic accuracy of BTP, Cys-C, and the GFR estimate for the detection of impaired GFR than serum creatinine (P <0.05). Compared to creatinine, BTP increased the diagnostic sensitivity by ∼30%, but it was not more sensitive than Cys-C or the Schwartz GFR estimate. Conclusions: BTP is superior to serum creatinine and an alternative for Cys-C to detect mildly reduced GFR in children, but it is not better than the Schwartz GFR estimate.

The seminal plasma components neutral alpha-glucosidase, carnitine, fructose, citrate, and polymorphonuclear granulocyte (PMN) elastase in 253 men were determined. The seminal plasma of 221 infertile men, a control group with proved fertility and 13 patients after vasectomy were investigated. The concentrations of free carnitine (212 versus 521 micromol/l, n = 219, P < 0.001), total carnitine (437 versus 743 micromol/l, n = 219, P < 0.001), and the activity of neutral alpha-glucosidase (15.1 versus 23.4 IU/l, n = 236, P < 0.05) were significantly reduced in the infertile patient group as compared to the fertile control group, the concentration of PMN elastase (102 versus 48 microg/l, n = 234, P < 0.05) being significantly increased in the infertile patients. In the patients after vasectomy the activity of neutral alpha-glucosidase was the only epididymal marker that was significantly reduced (4.3 versus 9. 8 IU/l, n = 35, P = 0.002) in comparison with the patients with testicular azoospermia. At a limit of 6 IU/l the sensitivity of the method was 92% and the specificity was 72%. Altogether, the epididymal markers were reduced in subfertile patients compared with the control group. For the differential diagnosis of azoospermia only the determination of the neutral alpha-glucosidase activity is useful.

Background: Diabetic nephropathy is the leading cause of end-stage renal disease in European countries and is associated with an enhanced renal synthesis of endothelin (ET)-1. ETs are – beside its potent vasoconstrictor properties – very potent profibrotic acting paracrine hormones especially in the kidney. Methods: We analyzed in rats with streptozotocin-induced diabetes the effects of an ETA-type (ETA) receptor antagonist (LU 135252) in comparison to a combined ETA/ETB receptor antagonist (LU 224332) on the expression of interstitial and glomerular collagen type I, III and IV as well as on fibronectin and laminin by quantitative immunohistochemistry using a computer-aided image analysis system. Global glomerular matrix deposition was analyzed after PAS staining. In addition to the morphometric examination of the kidneys, we also investigated GFR, urinary albumin and total protein excretion. The diabetic rats were treated for 36 weeks. Results: Treatment with either LU 135252 or LU 224332 normalized the amount of PAS-positive material within the glomeruli. The expression of glomerular fibronectin and type IV collagen was increased 36 weeks after induction of diabetes. The overexpression of these two matrix proteins within the glomeruli of diabetic rats was completely abolished by both ET receptor antagonists, whereas protein excretion was only reduced by about 50% as compared to diabetic rats without treatment. Conclusion: The present study indicates that ETA receptor antagonists as well as combined ETA/ETB receptor antagonists reduce proteinuria and completely normalize the renal matrix protein expression in hyperglycemic rats with streptozotocin-induced diabetes. The antifibrotic effect seems to be mediated via the ETA receptor. ET receptor antagonists might be a new approach in the treatment of diabetic nephropathy.

High permeability hemofiltration is a new approach in the adjuvant therapy of sepsis that facilitates the elimination of cytokines. HP-HF alternating with conventional hemofiltration is well tolerated. Further studies are needed to analyze whether HP-HF is able to mitigate the course of sepsis.

No abstract

No abstract

Background-It remains unclear whether the association between low birth weight and insulin resistance in adulthood has its origin in utero or whether it develops later in life depending on predisposition and exogenous factors. Methods and Results-Total glycosylated hemoglobin (TGH) was quantified at delivery in 1295 mother/child pairs serving as a surrogate of maternal and fetal glycemia. Multivariable regression analysis considering gestational age at delivery, the child's sex, maternal body mass index, and smoking during pregnancy revealed that an increase in TGH by 1% in the child was significantly associated with a mean birth weight reduction of 135 g (PϽ0.0001), whereas the same increase in the mother was associated with a mean birth weight increase of 88 g (PϽ0.0001). The ratio of fetal/maternal TGH suggests that lighter newborns have a higher percentage of TGH than would be expected from maternal TGH. Conclusions-The study demonstrates for the first time in a large population that there is an inverse association between TGH of a newborn and its birth weight. This might be due to increased insulin resistance in newborns with lower birth weight. Our data suggest that the pathophysiological mechanisms linking prenatal growth and postnatal sensitivity to insulin are present as early as before birth.