Birthweight and fetal glycosylated hemoglobin at birth in newborns carrying the GLUT1 XbaI gene polymorphism.

BACKGROUND: Low birthweight is an independent risk factor of glucose intolerance and type 2 diabetes in later life. Genetically determined insulin resistance and subsequently impaired glucose uptake might explain both reduced fetal growth and elevated blood glucose. The glucose transporter 1 (GLUT1) plays an important role for fetal glucose uptake as well as for maternal-fetal glucose transfer, and it has been associated with insulin resistance in adults. The present study hypothesized that the common fetal GLUT1 XbaI polymorphism might reduce fetal insulin sensitivity and/or glucose supply in utero, thus affecting fetal blood glucose and fetal growth. METHODS: A genetic association study was conducted at the obstetrics department of the Charité University Hospital, Berlin, Germany. 1191 white women were included after delivery, and all newborns were genotyped for the GLUT1 XbaI polymorphism. Total glycosylated hemoglobin was quantified, serving as a surrogate of glycemia during the last weeks of pregnancy. RESULTS: The analysis of this large population showed no significant differences in fetal glycosylated hemoglobin or birthweight for the different fetal GLUT1 XbaI genotypes. Only newborns carrying the mutated allele show the previously published inverse association between birthweight and glycosylated hemoglobin. CONCLUSIONS: The results suggest that there is no prenatal effect of the fetal GLUT1 XbaI polymorphism on fetal insulin sensitivity, intrauterine fetal glucose supply or fetal growth. However, the polymorphism seems to modulate the inverse interaction between birthweight and fetal glycemia.

A sudden death with lung embolism after inadvertent infusion of zinc oxide shake lotion.

A 74-year old woman in postoperative treatment after a colonic surgery died immediately after perfusion of about 1.5 mL of a white emulsion which was believed to contain 1% propofol via cardiac catheter into the right atrium. It was strongly suspected that a syringe with a zinc oxide shake lotion (consisting of 20% ZnO, 20% talc, 25% glycerol and 35% water) which was intended for external treatment had been mistaken for the propofol syringe. During autopsy, an anatomic cause of death could not be found. In order to exclude an intoxication and to determine the significance of the perfusion fluid in this context, toxicological and histological investigations were performed. Propofol and other drugs applied to the patient were found in therapeutic or sub-therapeutic range. However, in comparison to a control case, the zinc concentrations determined by AAS were about 200 times higher in lung tissue, 10 times higher in heart blood and 3-4 times higher in kidney and liver tissue. No increase was seen in venous blood. Histology showed a strong embolism of the lung tissue with birefingent sharp-edged crystals, which were identified as the talcum, and an amorphous component (ZnO). The same embolism was seen to a medium extent also in the brain sections and to a low extent in heart, liver, pancreas and kidney. Pulmonary embolism by talcum and zinc oxide was established as the cause of death which occurred by syringe swap due to insufficient security precautions in the drug administration. The results are discussed in context of pulmonary microembolism cases frequently described for drug addicts after injection of crashed talcum containing tablets.

Fetal and maternal peroxisome proliferator-activated receptor gamma2 Pro12Ala does not influence birth weight.

The association between the peroxisome proliferator-activated receptor (PPAR)gamma2 Pro12Ala polymorphism and insulin resistance is reported to depend on low birth weight. Low birth weight itself has been linked to type 2 diabetes and cardiovascular diseases in adulthood. We assessed whether the PPARgamma2 Pro12Ala polymorphism determines body size at birth and whether metabolic differences between the genotypes are already detectable in the newborn. This study was conducted at the obstetrics department of the Charité, Berlin, Germany. One thousand nine hundred thirty white woman/child pairs were consecutively included and genotyped. The newborn's weight, length, and head circumference were measured. Total glycated hemoglobin in blood served as a surrogate of fetal insulin resistance and glucose use. We found that neither the fetal nor the maternal Pro12Ala genotype determined body size or total glycated hemoglobin at birth. The results suggest that the PPARgamma2 Pro12Ala polymorphism is not relevant for intrauterine growth. Previously reported effects of PPARgamma2 Pro12Ala on insulin resistance seem to arise later in life.

Low birth weight, a risk factor for cardiovascular diseases in later life, is already associated with elevated fetal glycosylated hemoglobin at birth.

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 (P<0.0001), whereas the same increase in the mother was associated with a mean birth weight increase of 88 g (P<0.0001). 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.

Chronic cyclooxygenase-2 inhibition does not alter blood pressure and kidney function in renovascular hypertensive rats.

BACKGROUND: It has been shown that the macula densa participates in the regulation of increased renin expression in two-kidney one-clip (2K1C) renovascular hypertension. Prostaglandins might be one of the mediators of macula densa function, because the cyclooxygenase-2 (COX-2), one of the rate-limiting enzymes of the prostaglandin pathway, is upregulated in 2K1C renovascular hypertensive rats. We tested the effect of chronic COX-2 inhibition on blood pressure, urinary aldosterone excretion and kidney morphology, as well as kidney function. METHODS: Four groups were established: two groups of 2K1C renovascular hypertensive rats treated with the specific COX-2 inhibitor Celecoxib (cele) (15 mg/kg per day) or placebo immediately after operation, and two sham-operated control groups fed with Celecoxib or placebo. RESULTS: Long-term COX-2 inhibition in 2K1C renovascular hypertensive rats did not alter blood pressure at any point of time. Urinary aldosterone excretion was elevated by clipping the renal artery (2K1C, 8.1 +/- 1.9, versus controls, 3.6 +/- 0.5 ng/24 h; P = 0.05) but was not influenced by treatment with Celecoxib. Also, Celecoxib treatment did not alter glomerular filtration rate (GFR), serum sodium, serum creatinine, serum urea or proteinuria in 2K1C renovascular hypertensive rats. Interstitial fibrosis of the left clipped kidney was markedly reduced (2K1C, 6.19 +/- 0.83% versus 2K1C + cele 3.00 +/- 0.68% of total area; P = 0.012), whereas the interstitial fibrosis of the non-clipped kidney or the glomerulosclerosis of both kidneys were not affected by Celecoxib treatment. CONCLUSIONS: Celecoxib reduces the interstitial fibrosis of the clipped kidney. Blood pressure, urinary aldosterone excretion or whole kidney function were not affected in renal hypertensive rats.

Intermittent high permeability hemofiltration in septic patients with acute renal failure.

OBJECTIVE: High permeability hemofiltration (HP-HF) is a new renal replacement modality designed to facilitate the elimination of cytokines in sepsis. Clinical safety data on this new procedure is still lacking. This study investigates the effects of HP-HF on the protein and coagulation status as well as on cardiovascular hemodynamics in patients with septic shock. In addition, the clearance capacity for interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) is analyzed. DESIGN: Prospective, single-center pilot trial. SETTING: University hospital. PATIENTS: Sixteen patients with multiple organ failure (MOF) induced by septic shock were studied. INTERVENTION: Patients were treated by intermittent high permeability hemofiltration (iHP-HF; nominal cut-off point: 60 kilodaltons). Intermittent HP-HF was performed over 5 days for 12 h per day and alternated with conventional hemofiltration. MEASUREMENTS AND RESULTS: Intermittent HP-HF proved to be a safe hemofiltration modality in regard to cardiovascular hemodynamics and its impact on the coagulation status. However, transmembrane protein loss occurred and cumulative 12-h protein loss was 7.60 g (IQR: 6.2-12.0). The filtration capacity for IL-6 was exceptionally high. The IL-6 sieving coefficient approximated 1 throughout the study period. The total plasma IL-6 burden, estimated by area under curve analysis, declined over time ( p<0.001 vs baseline). The TNF-alpha elimination capacity was poor. CONCLUSIONS: 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.

TNF-alpha elimination with high cut-off haemofilters: a feasible clinical modality for septic patients?

BACKGROUND: Renal replacement therapies with high cut-off haemofilters are new approaches in the adjuvant therapy of sepsis. We analysed the cytokine elimination capacity of a newly developed polyflux high cut-off haemofilter. Different renal replacement therapies are compared and tested for their clinical feasibility. METHODS: Blood from healthy volunteers (n=15) was incubated for 4 h with 1 mg of endotoxin and then circulated through a closed extracorporeal circuit. A newly developed polyflux haemofilter (P2SX) was used. Haemofiltration, haemodialysis and albumin dialysis were tested. IL-1ra (17 kDa), interleukin-6 (IL-6) (28 kDa), tumour necrosis factor alpha (TNF-alpha) (51 kDa), albumin (64 kDa), creatinkinase (CK) (80 kDa) and IgG (140 kDa) were measured in blood and filtrates prior to the initiation and after 5 min, 1, 2 and 4 h. RESULTS: Haemofiltration was superior to haemodialysis in the clearance capacity of all substances when applied in the 1 l/h ultrafiltration mode. Increasing the ultrafiltration rate/dialysate flow from 1 to 3 l/h led to a significant increase in cytokine clearances (P<0.001). At 3 l/h the differences between haemofiltration and haemodialysis vanished and both techniques achieved comparable cytokine clearances. Median clearance values ranged between 25 and 54 ml/min for interleukin-1 receptor antagonist (IL-1ra), 23 and 42 ml/min for IL-6 and 15 and 28 ml/min for TNF-alpha. Albumin loss was highest in the haemofiltration group with albumin clearances ranging between 7 and 13 ml/min. Using diffusion instead of convection significantly reduced the loss of albumin (P<0.01 for 1 l/h, P<0.05 for 3 l/h). Albumin dialysis was able to completely inhibit albumin loss but cytokine clearance capacity was limited. CONCLUSIONS: High cut-off haemofilters achieve high clearances for inflammatory IL-6 and TNF-alpha. Due to the high protein loss in haemofiltration, dialysis in combination with balanced protein substitution seems to be a suitable approach for clinical trials.

Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis.

As a resident of early endosomal phagosomes, Mycobacterium tuberculosis is connected to the iron uptake system of the host macrophage. beta-2-microglobulin (beta2m) 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, beta2m 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, beta2m-deficient mice suffer from tissue iron overload. Here, we show that modulating the extracellular iron pool in beta2m-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 beta2m-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 beta2m-KO mice over MHC-I-KO mice, and (b) iron overload represents an exacerbating cofactor for tuberculosis.

Endothelin receptor A blockade reduces proteinuria and vascular hypertrophy in spontaneously hypertensive rats on high-salt diet in a blood-pressure-independent manner.

The renal endothelin (ET) system is involved in the pathogenesis of kidney fibrosis as well as blood pressure control by regulating tubular sodium excretion. Long-term effects of ETA receptor blockade on blood pressure and kidney function in spontaneously hypertensive rats (SHRs) on a high-salt diet are unknown. We treated SHRs on a 6% (w/v) NaCl sodium diet (SHR-S) for 48 weeks with the ETA antagonist LU 135252 (whose selectivity for ETA is 150 times greater than for ETB) with 10, 30 and 100 mg x kg(-1) x day(-1) or placebo. The ETA antagonist had at no time-point any effect on blood pressure. Glomerular filtration rate was normal in SHR-S and not altered by LU 135252. However, urinary albumin excretion was markedly reduced by the ETA antagonist (SHR-S, 145+/-50 mg/day; SHR-S+10 mg x kg(-1) x day(-1) LU 135252, 33+/-11 mg/day, P<0.05 versus SHR-S; SHR-S+30 mg x kg(-1) x day(-1) LU 135252, 55+/-16 mg/day and SHR-S+100 mg x kg(-1) x day(-1) LU 135252, 32+/-11 mg/day, P<0.05 versus SHR-S at both concentrations). Total urinary protein excretion was likewise significantly reduced by treatment with 10 mg.kg(-1).day(-1) LU 135252 (SHR-S, 0.25+/-0.06 g/day; SHR-S+10 mg x kg(-1) x day(-1) LU 135252, 0.089+/-0.01 g/day, P<0.05 versus SHR-S). The higher dosages of LU 135252 showed only a trend towards reduction of total urinary protein excretion. Computer-aided image analysis after haematoxylin/eosin and periodic acid-Schiff staining revealed that treatment with 10 mg x kg(-1) x day(-1) LU 135252 significantly reduces the media/lumen ratio of intrarenal arteries. Higher dosages of LU 135252 were less effective. Renal matrix protein synthesis in SHR-S was not altered by LU 135252. In conclusion, the renal ET system contributes in a blood-pressure-independent manner to the regulation of urinary protein excretion and renal vascular hypertrophy in SHR-S. Lower doses of the ETA antagonist were more effective, indicating that a potential additional blockade of the ETB receptor using higher doses of LU 135252 seems to oppose the beneficial effects of a sole ETA blockade. Urinary protein excretion is an independent risk factor of chronic renal failure, thus ETA antagonists might be a therapeutic tool to prevent proteinuria-induced chronic renal failure.

Beta-trace protein, cystatin C, beta(2)-microglobulin, and creatinine compared for detecting impaired glomerular filtration rates in children.

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 beta-trace protein (BTP) in comparison with cystatin C (Cys-C), beta(2)-microglobulin (beta(2)-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), beta(2)-MG (Tinaquant; Roche), and creatinine (enzymatic assay; Creatinine-PAP; Roche). RESULTS: Seventy-five children had reduced GFR (<90 mL x min(-1) x 1.73 m(-2)). One hundred fifty children (independent of gender and age) with values >90 mL x min(-1) x 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 beta(2)-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 approximately 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.