Atrial contraction is an important determinant of pulmonary venous flow

Pulmonary venous flow has two phases (systolic and diastolic) in normal subjects when studied by pulsed Doppler echocardiography. Only one phase of pulmonary venous flow (diastolic) was observed in six patients without synchronous atrial contraction (four patients with atrial fibrillation and two with complete atrioventricular [AV] block). This pattern reversed to normal (biphasic) when AV synchrony was reestablished by cardioversion to sinus rhythm in patients with atrial fibrillation and by AV sequential pacing in patients with complete AV block. Thus, both atrial and ventricular contraction and relaxation are important determinants of pulmonary venous flow.     

Early neonatal group B streptococcal disease: degree of colonisation as an important determinant

During a period of 5 years (1 January 1977 to 1 January 1982) 145 infants colonised with group B streptococci (GBS) were admitted to the neonatal intensive care unit of the University Children's Hospital, Utrecht. In 87 of these infants (60%) vertical transmission of GBS was established; in 43 of these 87 infants (49%) the degree of colonisation was moderate to heavy. Early-onset (EO) GBS disease arose in 21 of 145 infants (attack rate: 14.5%). Of the 43 infants moderately to heavily colonised with GBS, however, 19 suffered from EO GBS disease (attack rate: 44.2%), whereas there were only two cases among the 44, lightly colonised infants (attack rate: 4.5%), a highly significant difference (P less than 0.0005). Similarly, probable sepsis (PS), defined as signs and symptoms of sepsis but without positive blood cultures, was observed significantly more often in moderately to heavily colonised infants (15/43, attack rate: 34.9%) compared with those lightly colonised (4/44, attack rate: 9.1%) (P less than 0.005). Infants moderately to heavily colonised with GBS at birth appear to have a significantly higher risk of developing serious GBS disease (EO or PS) than do infants only lightly colonised.     

Discrepancies between genotype and phenotype in hematology: an important frontier.

An African American male infant with sickle cell disease has a devastating stroke; an African American soldier is surprised when he is informed that he has sickle cell disease. They are both homozygous for the same mutation. An Ashkenazi Jewish woman with Gaucher disease has a huge spleen and severe thrombocytopenia; her older brother, homozygous for the same 1226G glucocerebrosidase mutation, is found on routine examination to have a barely palpable spleen tip. The fact that clinical manifestations of genetic diseases can vary widely among patients has been recognized for many decades. In the past, however, it could often be attributed to the pleomorphic nature of mutations of the same gene: the patient with severe disease, it was averred, must have a different mutation than the one with mild disease. Even before a precise definition of mutations could be achieved at the DNA level, such an explanation did not serve to clarify the differences that existed between siblings with the same autosomal recessive disease. Such siblings must surely be carrying the same 2 disease-producing alleles. With the advent of sequence analysis of genes, the great extent of phenotype variation in patients with the same genotype has come to be more fully appreciated, but understanding of why it occurs continues to be meager. It is the purpose of this review to explore some of the variations in phenotype seen by hematologists in patients with identical mutations, to indicate where some progress has been made, and to suggest how understanding in this important area may be expanded.     

Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo.

In the present paper, we characterize an antibody, mAb BV13, directed to mouse vascular endothelial (VE)-cadherin, a major adhesive protein of interendothelial adherens junctions. When added to cultured endothelial cells, BV13 induces a redistribution of VE-cadherin from intercellular junctions. VE-cadherin redistribution did not change the localization of platelet endothelial cell adhesion molecule or tight junction markers such as zonula occludens 1, cingulin, and junctional adhesion molecule. Intravenous administration of mAb BV13 induced a concentration- and time-dependent increase in vascular permeability in heart and lungs. By electron microscopy, interstitial edema and accumulation of mixed types of inflammatory cells in heart and lungs were observed. Injection of (rhodamine-labeled) Ricinus communis I lectin showed focal spots of exposed basement membrane in the alveolar capillaries and in some larger pulmonary vessels. These data indicate that VE-cadherin is required for vascular integrity and normal organ functions.     

Clinical and hematologic aspects of hemoglobin E beta-thalassemia

Hemoglobin E beta-thalassemia is an important cause of childhood chronic disease in Southeast Asia. It is characterized by the presence of hemoglobin E and F, and the amount of hemoglobin E ranges from 35% to 75%. The patients are generally classified as having thalassemia intermedia because they have inherited a beta-thalassemia allele and hemoglobin E, which acts as a mild beta+-thalassemia. However, a remarkable variability in the clinical expression, ranging from a mild form of thalassemia intermedia to transfusion-dependent conditions, is observed. Severe hemoglobin E beta-thalassemia may have clinical features of thalassemia major. Phenotypes of thalassemia major can be predicted from the early onset of clinical symptoms and the requirement of regular blood transfusion from infancy for survival. Coinheritance of alpha-thalassemia alleviated the severity of beta-thalassemia disease in patients with at least one allele of mild beta-thalassemia genotype.     

Serum lactate dehydrogenase is an important risk determinant in acute lymphocytic leukemia

Pretreatment serum total lactate dehydrogenase (LDH) activity was measured in 341 adult patients (greater than 15 years old) with acute lymphocytic leukemia (ALL) in order to assess its prognostic value. Failure, death during induction and remission were not related to LDH. In contrast, a negative and continuous relationship was found between LDH and relapse-free survival. Though LDH activity was significantly higher in cases with already established risk factors such as high WBC count, FAB L3 cytotype, mature B-cell phenotype, and central nervous system involvement, LDH was confirmed to be the strongest predictor of remission duration by multivariate analysis. This study provides a definitive confirmation of the negative prognostic value of LDH in adult ALL.     

Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells

Detailed studies of tumor cell-associated procoagulants and fibrinolytic factors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directly determine whether fibrin(ogen) or plasmin(ogen) are determinants of the metastatic potential of circulating tumor cells, this study examined the impact of genetic deficits in each of these key hemostatic factors on the hematogenous pulmonary metastasis of 2 established murine tumors, Lewis lung carcinoma and the B16-BL6 melanoma. In both tumor models, fibrinogen deficiency strongly diminished, but did not prevent, the development of lung metastasis. The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tumor growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the lung. The specific thrombin inhibitor, hirudin, further diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice, although the inhibitor had no apparent effect on tumor cell proliferation in vitro. The absence of plasminogen and plasmin-mediated fibrinolysis had no significant impact on hematogenous metastasis. The authors concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells. Furthermore, thrombin appears to facilitate tumor dissemination through at least one fibrin(ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct hemostatic factors might be beneficial in the containment of tumor metastasis.     

Dynamic component of sports is an important determinant factor of heart rate recovery

Objective

It is usually suggested that life expectancy of top athletes especially in endurance sports is longer than that of sedentary people. On the other hand, heart rate recovery (HRR) after exercise is an independent risk factor for cardiovascular disease and mortality, but differences in HRR between various top athletes are unclear. We examined HRR in various top athletes to clarify a role of HRR that may affect their life expectancy.

Methods

HRR was defined as the difference between the heart rate at peak exercise and that at 2 min after the finish of exercise using symptom-limited maximal graded bicycle ergometer exercise testing. The relationships between HRR with the grade of static and dynamic component of classification of sports, age, and body mass index (BMI) were estimated.

Subjects

The subjects were 720 male athletes participating in the National Sports Festival Japan in 2005–2008 and age-matched 28 sedentary controls.

Results

HRR was significantly correlated (p < 0.0001) with the higher grade of dynamic component of sports, younger age, and lower BMI in both univariate and multivariate analysis.

Conclusions

HRR of top athletes is predicted by increased dynamic component of sports, younger age, and lower BMI.     

Linkage analysis of the hemoglobin F determinant(s) in an australian hemoglobin lepore (Boston) kindred

Genetic determinants that influence the levels of fetal hemoglobin (Hb F) in a single Australian kindred with heterozygous Hb Lepore (Boston) were sought. There were 22 affected individuals, some of whom had high Hb F and others with Hb F levels within the normal range. Family members were typed for restriction fragment length polymorphisms (RFLPs) associated with the β-globin gene complex and the nearby genetic markers D11S12, INS, HRAS, and PTH. Prior to linkage analysis, a cohort of 54 unrelated Hb Lepore heterozygotes was analyzed to establish the distribution of Hb F levels measured by alkaline denaturation (Hb F_AD). An Hb F level of >2.0% was used as the cutoff point for linkage analysis of the putative hereditary persistence of fetal hemoglobin (HPFH) determinant(s) in this kindred. Positive peak lod scores were obtained for the entire pedigree between the HPFH determinant and Hb Lepore (Z_m+1 = 2.35 at θ = 0.15) and the β-globin cluster (HBBC) (Z_m+1 = 2.38 at θ = 0.20) marker loci, indicating the possibility of an independent HPFH gene at some distance from the β-globin gene cluster. However, most of these lod scores result from the non-Hb Lepore members of the family who, with one exception, do not have high Hb F, and when only those affected with Hb Lepore were analyzed the lod score values at these loci fell to small positive values (<1.0). These data do not support an independent cosegregating HPFH determinant separate from the Hb Lepore locus in this pedigree. The results favor a pleiotropic effect of the Hb Lepore lesion itself influencing Hb F levels by genetic or environmental factors not yet elucidated.     

Membrane-associated sickle hemoglobin: a major determinant of sickle erythrocyte rigidity

Micropipette aspiration tests on single erythrocytes have previously shown that the static rigidity (membrane shear modulus) of oxygenated sickle cells increased with increasing hemoglobin concentration, whereas the rigidity of normal cells was independent of hemoglobin concentration. Moreover, it was observed that after mechanical extension, sickle cells exhibited persistent deformation more frequently and to a greater extent than normal cells. To ascertain if differences in association of normal and sickle hemoglobin with the membrane could account for these observations, we measured rheologic properties of normal membranes reconstituted with sickle hemoglobin and sickle membranes reconstituted with normal hemoglobin. The static rigidity of normal ghosts reloaded with sickle hemoglobin was higher than those of either normal ghosts reloaded with normal hemoglobin or native normal cells. On the other hand, the increased rigidity of native sickle cells decreased to near-normal values following reconstitution with normal hemoglobin. Furthermore, we observed that normal ghosts reconstituted with sickle hemoglobin exhibited persistent bumps after mechanical extension, but no bumps formed on normal ghosts reconstituted with normal hemoglobin. Moreover residual bumps were not produced on sickle cells reloaded with normal hemoglobin. Since mechanical characteristics peculiar to sickle cells could be induced in normal cells by incorporation of sickle hemoglobin, and since normal characteristics could be restored to sickle cells by incorporation of normal hemoglobin, we suggest that the interaction of sickle hemoglobin with the cell membrane is responsible for augmented static rigidity of oxygenated sickle erythrocytes.     

Physical inactivity is an important lifestyle determinant of insulin resistance in hypertensive patients

The purpose of the study is to assess the relative impact of lifestyle factors including physical inactivity, cigarette smoking, and alcohol intake on insulin resistance in hypertensive patients. In total, 872 hypertensive patients, of Chinese and Japanese origin, from the Stanford Asia and Pacific Program for Hypertension and Insulin Resistance were included for the current analysis. Homeostasis model assessment for insulin resistance (HOMA-IR) and the insulin sensitivity index ISI0,120 were chosen as surrogate measures of insulin resistance. Standardized interview-administered questionnaires were used to obtain information on demographic and lifestyle characteristics. The sedentary hypertensive patients were more insulin resistant than the non-sedentary hypertensive. There were significant differences in Log (HOMA-IR) (0.06-unit increases, p < 0.01) and Log (ISI0,120) (0.05-unit decreases, p < 0.01) between sedentary and non-sedentary hypertensive patients after controlling demographic variables. There were no differences in insulin sensitivity in subjects with different smoking status. Neither smoking nor alcohol intake was persistently associated with insulin resistance in the analysis. Our results suggest that physical inactivity is an important lifestyle determinant of insulin resistance in hypertensive patients. The influences of smoking and alcohol intake on insulin resistance are less significant than physical inactivity in hypertensive subjects.     

Interaction between water and polar groups of the helix backbone: an important determinant of helix propensities

We report an enthalpic factor involved in determining helix propensities of nonpolar amino acids. Thermal unfolding curves of the five 13-residue peptides, Ac-KA4XA4KGY-NH2 (X = Ala, Leu, Ile, Val, Gly), have been measured by using CD in water/trifluoroethanol (TFE) mixtures. The peptide helix contents show that the rank order of helix propensities changes with temperature: although Ala has the highest helix propensity at 0 degrees C in all TFE concentrations, it is lower than Leu, Ile, and Val at 50 degrees C in 20% TFE. This change is attributed to shielding by nonpolar side chains of the interaction between water and polar groups in the helix backbone for the following reasons. (i) Helix content is directly related to helix propensity for these designed peptides because side-chain-side-chain interactions are absent. (ii) The change in rank order with temperature is enthalpic in origin: in water, the apparent enthalpy of helix formation calculated from the thermal unfolding curves varies widely among the five peptides and has the same rank order as the helix propensities at 0 degrees C. The rank order does not result from burial of nonpolar surface area because the calculated heat capacity change (DeltaCp) on helix formation is opposite in sign from the expected DeltaCp. (iii) A nonpolar side chain can exclude water from interacting with helix polar groups, according to calculations of water-accessible surface area, and the polar interaction between water and peptide polar groups is entirely enthalpic, as shown by amide transfer data.     

Electrostatic interactions in the channel cavity as an important determinant of potassium channel selectivity

Potassium channels are membrane proteins that allow the passage of potassium ions at near diffusion rates while severely limiting the flux of the slightly smaller sodium ions. Although studies thus far have focused on the narrowest part of the channel, known as the selectivity filter, channels are long pores with multiple ions that traverse the selectivity filter, the water-filled central cavity, and the rest of the pore formed by cytoplasmic domains. Here, we present experimental analyses on Kir3.2 (GIRK2), a G protein-activated inwardly rectifying potassium (Kir) channel, showing that a negative charge introduced at a pore-facing position in the cavity (N184) below the selectivity filter restores both K(+) selectivity and inward rectification properties to the nonselective S177W mutant channel. Molecular modeling demonstrates that the negative residue has no effect on the geometry of the selectivity filter, suggesting that it has a local effect on the cavity ion. Moreover, restoration of selectivity does not depend on the exact location of the charge in the central cavity as long as this residue faces the pore, where it is in close contact with permeant ions. Our results indicate that interactions between permeant ions and the channel cavity can influence ion selectivity and channel block by means of an electrostatic effect.     

Blood flow is an important determinant of forearm glucose uptake following a mixed meal

Abstract. Insulin-mediated vasodilation has been suggested to be of importance for glucose uptake during normoglycemic hyperinsulinemia. If this also is valid after an ordinary mixed meal remains to be evaluated. Forearm blood flow (FBF) and forearm glucose uptake change (evaluated by venous occlusion plethysmography) and glucose arteriovenous differences were evaluated over 120 minutes in 10 healthy volunteers following an ordinary mixed meal (700–900 kcal, 34% of energy from fat). Fasting arterial glucose level was 4.9±0.9 mmol/l, and the maximum glucose level was reached 30 minutes after the start of ingestion (6.6±0.8 mmol/l, p<0.0001). Plasma insulin levels were increased four-fold. FBF increased rapidly within 20 minutes after the start of ingestion and reached its maximum after 50 minutes (94% higher than baseline level, p<0.01). After 2 hours FBF was still substantially elevated (75% above baseline level, p<0.01). Forearm glucose uptake increased fivefold already after 20 minutes (p<0.01). During the 2 hours, the increase in FBF contributed to 41% of the forearm glucose uptake (p<0.05). The present study showed that the increase in FBF seen after an ordinary mixed meal is important for the change in forearm glucose uptake. These results support the view that modulation of limb blood flow is a determinant of glucose uptake.     

Atopic phenotype is an important determinant of immunoglobulin E-mediated inflammation and expression of T helper cell type 2 cytokines to ascaris antigens in children exposed to ascariasis

Studies have shown a strong inverse relationship between atopy and geohelminth infection, indicating that atopy may protect against geohelminth infection. Resistance to ascariasis in atopic individuals may occur through greater immunoglobulin E-mediated responses and expression of T helper cell type 2 (Th2) cytokines to parasite antigens. To investigate the effect that atopy has on the immune response to Ascaris antigens, school-age children were recruited from rural schools in Ecuador. Immunologic variables were compared between children stratified by atopic and/or A. lumbricoides-infection status; the variables included cytokine expression by peripheral-blood mononuclear cells (PBMCs) and histamine release in response to Ascaris antigens. Atopic children had both greater frequencies of PBMCs expressing interleukin (IL)-4 and IL-5 and enhanced histamine release, compared with those in nonatopic children. Stratification by atopic and A. lumbricoides-infection status revealed the greatest histamine and Th2 cytokine responses in the stratum of atopic, noninfected children. Multivariate regression analyses showed significant effects for atopic status but not for infection status on Th2 cytokine expression and histamine release.     

Platelet von Willebrand factor: an important determinant of the bleeding time in type I von Willebrand's disease

We studied 17 patients with moderate to mild type I von Willebrand's disease (vWd) and correlated the bleeding time with the plasma von Willebrand factor antigen (vWf Ag), the plasma vWf activity (ristocetin cofactor), the platelet vWf Ag, and the platelet vWf activity. We found an excellent correlation between the bleeding time and the platelet vWf activity and, to a lesser extent, between the bleeding time and the platelet vWf Ag. The length of the bleeding time was inversely proportional to the level of the platelet vWf (P less than .001) or, to a lesser extent, the platelet vWf Ag (P less than .05). The plasma vWf Ag and activity did not correlate significantly with the bleeding time. These studies indicate that the platelet vWf is one of the important bleeding time factors in type I vWd and that the platelet vWf plays an important role in the early steps of hemostasis.     

The MDR phenotype in hematologic malignancies: prognostic relevance and future perspectives

 The multidrug resistant (MDR) phenotype has been suspected as a major cause of treatment failure in hematologic malignancies. Numerous studies have investigated the expression of the MDR1 gene product, P-glycoprotein, in leukemia, lymphoma and myeloma. Studies in myelogenous leukemia and myeloma have so far provided best evidence for a significant correlation between P-glycoprotein expression and response to chemotherapy, although large discrepancies in the proportion of positive cells limit any definite conclusion. Differences in P-glycoprotein detection techniques and methodology may account for the divergent results thus emphasizing the necessity for standardized methods of detection. Despite this, encouraging clinical results have been obtained using MDR modulators in combination with conventional chemotherapy to inhibit the activity of the P-glycoprotein pump. The paper summarizes currently available clinical data and provides guidelines for future trials aimed to reverse the MDR phenotype. The potential of idarubicin to overcome the MDR phenotype is also discussed. Received: 20 November 1995 / Accepted: 18 January 1996     

Serum growth hormone (GH)-binding protein/receptor: an important determinant of GH responsiveness.

Individual growth rates (or responses to GH therapy) and adult heights vary over a wide range. The reasons for this variation are poorly understood. Based on the reciprocal relationship between GH production and serum GH-binding protein/receptor (GH-BP), we hypothesized that genetic growth potential was achieved by a specific combination of GH-BP/receptor and GH production in each individual. To address the question whether GH production regulates GH-BP, or vice versa, we studied GH-deficient children, where one of the parameters, GH exposure, could be controlled through exogenous administration. Forty-three untreated prepubertal GH-deficient children were studied before and after 6 and 12 months of GH replacement therapy (0.18 mg/kg.week). Growth velocity, height, bone age, weight and their respective Z scores, serum GH-BP, and serum insulin-like growth factor I (IGF-I) were measured at each time point. The patients responded with significant increases in serum IGF-I, age-adjusted growth velocity, and height (P < 10(-6) for all). Before therapy, GH-BP correlated directly with chronologic and bone age (P < 10(-4), but not with either growth velocity or IGF-I. In contrast, GH-BP correlated strongly with the response to therapy whether assessed as the incremental change in IGF-I (P < 10(-6)) or as the increase in growth velocity (P approximately 0.003). GH treatment had no consistent effect on GH-BP/receptor levels. These findings support the concept that the GH-BP/receptor endowment is characteristic for an individual and plays a pivotal role in somatic growth. The GH-BP/receptor system and its ontogeny appears relatively independent of regulation by GH. Differences in individual GH-BP/GH receptor complement account for some of the variability in the response to GH, and GH-BP levels may serve as a predictor for the degree of response. The reciprocal relationship between GH production and GH-BP in normal subjects probably results from adjustment of GH secretion to accommodate the prevailing GH-BP/receptor environment.     

Inflammatory status as an important determinant of heat shock protein 70 serum concentrations during aging

Heat shock proteins (Hsp) form a large family of proteins that are ubiquitously present in all organisms. In the absence of destabilising stimuli, Hsp are expressed at low levels, but their expression can be highly induced by various noxious conditions such as heat, oxygen stress and infection. Hsp have been reported to interfere with inflammatory processes and their induction is well known to decrease with aging. In the present study we have investigated Hsp 70 serum concentrations using an optimised ELISA in elderly patients, recruited from a geriatric University Hospital ward. Our results portray positive correlations between the serum levels of Hsp 70 and various markers of inflammation (monocyte count, serum concentration of TNF-alpha, plasma concentrations of C-reactive protein, and fibrinogen), explaining the difference in Hsp 70 serum concentrations in these subjects with various degrees of inflammation. We conclude that Hsp 70 is involved in inflammatory diseases and that the serum level of Hsp 70 is directly linked to the inflammatory status of the subject. However, the nature of this relationship remains to be elucidated.