Endothelial arginase II: a novel target for the treatment of atherosclerosis

Oxidized low-density lipoproteins increase arginase activity and reciprocally decrease endothelial NO in human aortic endothelial cells. Here, we demonstrate that vascular endothelial arginase activity is increased in atherogenic-prone apolipoprotein E-null (ApoE(-/-)) and wild-type mice fed a high cholesterol diet. In ApoE(-/-) mice, selective arginase II inhibition or deletion of the arginase II gene (Arg II(-/-) mice) prevents high-cholesterol diet-dependent decreases in vascular NO production, decreases endothelial reactive oxygen species production, restores endothelial function, and prevents oxidized low-density lipoprotein-dependent increases in vascular stiffness. Furthermore, arginase inhibition significantly decreases plaque burden. These data indicate that arginase II plays a critical role in the pathophysiology of cholesterol-mediated endothelial dysfunction and represents a novel target for therapy in atherosclerosis.     

The pathologic correlates of the electrocardiogram: complete left bundle branch block

To assess whether gross pathologic differences exist between hearts with left bundle branch block (LBBB) and left-axis deviation (LAXD) and those with LBBB and a normal frontal plane axis, we examined 70 hearts with LBBB in a series of 1410 sequential dissections (5%). Thirty-two hearts had LAXD and 34 had normal axes on the correlative ECG. Left ventricular enlargement occurred frequently (93%). No significant differences were found in age distribution, left ventricular weight, coronary anatomy or infarct location. Quantitative analysis revealed larger inferoposterolateral and apical infarcts in hearts with LBBB and LAXD (p less than 0.01). The accuracy of various electrocardiographic signs of left ventricular enlargement and myocardial infarction in the presence of LBBB was assessed. Voltage criteria and QRS duration poorly define anatomic chamber enlargement. Anterior infarction is suggested by a q or pathological Q wave in lead I, a q wave in leads I, V5 and V6, or notched S waves in V3 or V4. Pathologic q waves or ST shifts in the inferior leads have high diagnostic specificity but low sensitivity for inferior infarction.     

Red cell distribution width (RDW) in the diagnosis of iron deficiency with microcytic hypochromic anemia

Objective  To study the utility of red cell distribution width (RDW) in the diagnosis of iron deficiency among children with microcytic hypochromic anemia. Methods  151 children (6 months-12 years) with microcytic (MCV<75 fl) anemia were classified into iron deficient (IDA) and non-iron deficient anemia (non-IDA) on the basis of serum ferritin and total iron binding capacity (TIBC). RDW values were obtained on an automated hematology analyzer. Receiver operator curves (ROC) were constructed and the utility of RDW in diagnosis of iron deficiency was studied. Results  The mean RDW value was 18.37±2.22% in IDA group (97 children) compared to 16.55±1.51 % in the non-IDA group (54 children) (p<0.0001, unpaired t test). In IDA group, the mean RDW value was 16.60±1.78%, 17.95±1.91% and 20.55±1.32% among mild, moderate and severely anemic children (p<0.0001, ANOVA test). The corresponding values in non-IDA group were 16.03±1.25%, 16.76±1.20% and 16.77±2.68% respectively (p=0.269, ANOVA test). At a cut-off value of 17.4%, as obtained from the ROC curve, the sensitivity and specificity of RDW in diagnosis of IDA were 81.0% and 53.4% and a positive and negative predictive value of 63.0% and 72.2% respectively. Conclusion  RDW has a limited specificity for diagnosis of IDA among children with microcytic hypochromic anemia.     

Analysis of PR subintervals in normal subjects and early studies in patients with abnormalities of the conduction system using surface His bundle recordings

Utilizing several different approaches to noise reduction, satisfactory beat by beat His bundle activity was recorded from the chest surface in 41 (80%) of 52 normal subjects. Surface atrial to His intervals (PAH) and His to ventricular intervals (HV) were measured in this group and compared with subintervals of the PR segment recorded endocardially from 47 persons with normal electrophysiologic findings. A recent modification in the selection algorithm allows on-line identification of the four of five possible recording sites for utilization in a spatial summation. The ability to record in less favorable circumstances has been improved to the extent that records of suitable clarity for measurement were also obtained in 17 (77%) of 22 individuals with conduction system abnormalities. Comparison of the surface and endocardially acquired data in the normal group reveals no statistically significant difference in the surface acquired PAH and endocardially acquired high right atrial to His (HRAH) intervals, nor in the HV intervals. In a small subset of patients data were acquired by both techniques and no significant differences were found. Thus, when programmed stimulation or endocardial mapping is not required to answer specific clinical questions, in the majority of persons it is possible to record meaningful subintervals from the body surface from each cardiac cycle. Additionally, in instances in which surface P wave activity is obscure in the routine electrocardiogram, this technique enhances atrial electrical activity.     

Spruce budworm (Choristoneura fumiferana) juvenile hormone esterase: hormonal regulation, developmental expression and cDNA cloning

We have used the differential display of mRNAs technique to identify Choristoneura fumiferana genes that are induced by juvenile hormone I (JH I). Of the six PCR products identified, one bound to a 2.8-kb mRNA from CF-203 cells whose abundance increased when the cells were grown in the presence of JH I. The same 2.8-kb mRNA decreased to undetectable levels when the CF-203 cells were grown in the presence of 20-hydroxyecdysone (20E). The PCR fragment probe also detected a 2.8-kb mRNA in the C. fumiferana larval tissues. This 2.8-kb mRNA was present on the first day of the first, third, fourth, fifth and sixth larval and pupal stadia, but was conspicuously absent on the first day of the second larval stadium, as well as during the intermolt periods of the first to fifth instar larval stages. In the sixth instar larvae the 2.8-kb mRNA was detected in the fat body, epidermis and midgut during the intermolt period. The PCR fragment was used as a probe to screen a cDNA library. The deduced amino acid sequence of this 2.8-kb cDNA clone showed similarity with the deduced amino acid sequences of Heliothis virescens juvenile hormone esterases (HvJHE). The deduced amino acid sequence of the cDNA clone contained all five functional motifs that are present in most of esterases, proteases and lipases. The cDNA clone was expressed in the baculovirus expression system, producing a protein that showed JHE activity.     

Nutritional mismatch in postnatal life of low birth weight rat offspring leads to increased phosphorylation of hepatic eukaryotic initiation factor 2 α in adulthood

Objective

Epidemiological studies have established that low birth weight offspring, when faced with a nutritional mismatch in postnatal life, have an increased risk of developing the metabolic syndrome. Our laboratory and others have demonstrated that maternal protein restriction (MPR) leads to high cholesterol and insulin resistance in the offspring due to impaired liver function, though the underlying molecular mechanisms remain elusive. Recent in vitro studies have associated decreased phosphorylation of Akt1 (Serine 473), a marker of insulin sensitivity, with increased phosphorylation of eukaryotic initiation factor (eIF)-2α (Serine 51), a key regulator of protein translation attenuation. The main aim of the study was to determine whether nutritional mismatch in MPR offspring leads to elevated phospho-eIF2α (Ser51) levels in the liver.

Materials/Methods

To investigate if this occurs long-term in MPR offspring, pregnant Wistar rats were fed a control (20%) protein diet (control) or a low (8%) protein diet during pregnancy and postnatal life (LP1), or during pregnancy and lactation (LP2).

Results

At postnatal day 130, LP2 offspring exhibited increases in hepatic phosphorylation of eIF2α (Ser51) concomitant with decreases in the phosphorylation of Akt1 (Ser473), while LP1 offspring exhibited the converse relationship. Interestingly, in embryonic day 19 livers derived from control or MPR pregnancy, no changes in eIF2α (Ser51) or Ak1 (Ser473) phosphorylation were observed.

Conclusion

Collectively, our data provide robust evidence that phosphorylation of eIF2α (Ser51) is inversely correlated with phosphorylated Akt1 (Ser473) in vivo. Moreover, this study demonstrates that this inverse relationship is adversely influenced in these MPR offspring by a mismatch in the postnatal nutritional environment.