scholarly journals Fetal hemoglobin in acute and chronic states of erythroid expansion

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 227-233 ◽  
Author(s):  
CA Blau ◽  
P Constantoulakis ◽  
A al-Khatti ◽  
E Spadaccino ◽  
E Goldwasser ◽  
...  
Keyword(s):  
Correlation Coefficient ◽  
Intravenous Administration ◽  
Fetal Hemoglobin ◽  
High Dose ◽  
Subcutaneous Route ◽  
Response Form ◽  
Hbf Induction ◽  
The Mean ◽  
Erythroid Maturation ◽  
Reticulocyte Production

Abstract Physiologic principles underlying the differences in fetal hemoglobin (HbF) induction between acute and chronic states of erythroid expansion are poorly understood. Whereas abrupt erythroid expansion is characterized by a high proportion of reticulocytes coexpressing adult and fetal globin (F reticulocytes), HbF levels wane with chronic erythropoietic stimulation. To investigate this phenomenon, we used various schedules of erythropoietin (epo) administration in primates. Acute intravenous epo administration promoted a 2- to 10-fold preferential induction of F reticulocytes compared with total reticulocytes. Total reticulocyte and F reticulocyte production were significantly correlated (correlation coefficient .41 to .74). With chronic epo administration, preferential F reticulocyte production was lost, and there was no correlation between reticulocyte and F reticulocyte production (correlation coefficient -.03). The mean percentage of F reticulocytes did not change between acute and chronic schedules of epo administration. The subcutaneous route of high-dose (3,000 U/kg) epo administration was as effective as intravenous administration in the induction of HbF. Reticulocyte and F reticulocyte responses to increasing epo doses were found to be saturable. These results suggest that the kinetics rather than absolute levels of reticulocyte and F reticulocyte response form the basis for preferential F reticulocyte induction with acute erythropoietic stimulation, and they support the hypothesis that F reticulocytes arise from a relatively rapid pathway of erythroid maturation.

scholarly journals Fetal hemoglobin in acute and chronic states of erythroid expansion

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 227-233
Author(s):  
CA Blau ◽  
P Constantoulakis ◽  
A al-Khatti ◽  
E Spadaccino ◽  
E Goldwasser ◽  
...  
Keyword(s):  
Correlation Coefficient ◽  
Intravenous Administration ◽  
Fetal Hemoglobin ◽  
High Dose ◽  
Subcutaneous Route ◽  
Response Form ◽  
Hbf Induction ◽  
The Mean ◽  
Erythroid Maturation ◽  
Reticulocyte Production

Physiologic principles underlying the differences in fetal hemoglobin (HbF) induction between acute and chronic states of erythroid expansion are poorly understood. Whereas abrupt erythroid expansion is characterized by a high proportion of reticulocytes coexpressing adult and fetal globin (F reticulocytes), HbF levels wane with chronic erythropoietic stimulation. To investigate this phenomenon, we used various schedules of erythropoietin (epo) administration in primates. Acute intravenous epo administration promoted a 2- to 10-fold preferential induction of F reticulocytes compared with total reticulocytes. Total reticulocyte and F reticulocyte production were significantly correlated (correlation coefficient .41 to .74). With chronic epo administration, preferential F reticulocyte production was lost, and there was no correlation between reticulocyte and F reticulocyte production (correlation coefficient -.03). The mean percentage of F reticulocytes did not change between acute and chronic schedules of epo administration. The subcutaneous route of high-dose (3,000 U/kg) epo administration was as effective as intravenous administration in the induction of HbF. Reticulocyte and F reticulocyte responses to increasing epo doses were found to be saturable. These results suggest that the kinetics rather than absolute levels of reticulocyte and F reticulocyte response form the basis for preferential F reticulocyte induction with acute erythropoietic stimulation, and they support the hypothesis that F reticulocytes arise from a relatively rapid pathway of erythroid maturation.

scholarly journals Fetal hemoglobin levels and morbidity in untransfused patients with β-thalassemia intermedia

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 364-367 ◽  
Author(s):  
Khaled M. Musallam ◽  
Vijay G. Sankaran ◽  
Maria Domenica Cappellini ◽  
Lorena Duca ◽  
David G. Nathan ◽  
...  
Keyword(s):  
Strong Association ◽  
Fetal Hemoglobin ◽  
Laboratory Measurements ◽  
Thalassemia Intermedia ◽  
Ineffective Erythropoiesis ◽  
Total Hemoglobin ◽  
History Of ◽  
Hbf Induction ◽  
The Mean ◽  
Hbf Level

To evaluate the association between fetal hemoglobin (HbF) levels and morbidity in β-thalassemia intermedia (TI), we analyzed data from 63 untransfused patients who had also never received HbF induction therapy. Patient records were reviewed for any history of 10 predefined morbidities. Laboratory measurements for markers of ineffective erythropoiesis were also obtained. The mean age of patients was 32.1 years, 47.6% were males, and the median HbF level was 37.2%. HbF levels correlated positively with total hemoglobin, yet negatively with growth differentiation factor-15 and non–transferrin-bound iron levels. Median HbF levels were significantly lower in patients with the majority of evaluated morbidities than in those without. There was a strong negative adjusted linear correlation between the HbF level and the total number of morbidities (R2 = 0.825, P < .001). The HbF threshold of 63.7% had 95.5% sensitivity and 100% specificity for ensuring absence of morbidity. There exists a strong association between HbF levels and morbidity in the subset of untransfused patients with TI.

scholarly journals ZNF410 represses fetal globin by devoted control of CHD4/NuRD

2020 ◽  
Author(s):  
Divya S. Vinjamur ◽  
Qiuming Yao ◽  
Mitchel A. Cole ◽  
Connor McGuckin ◽  
Chunyan Ren ◽  
...  
Keyword(s):  
Adult Stage ◽  
Fetal Hemoglobin ◽  
Therapeutic Index ◽  
Regulatory Elements ◽  
Globin Genes ◽  
Binding Motifs ◽  
Cellular Toxicity ◽  
Hbf Induction ◽  
Erythroid Maturation ◽  
Genomic Clusters

AbstractMajor effectors of adult-stage fetal globin silencing include the transcription factors (TFs) BCL11A and ZBTB7A/LRF and the NuRD chromatin complex, although each has potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here through CRISPR screening we discover ZNF410 to be a novel fetal hemoglobin (HbF) repressing TF. ZNF410 does not bind directly to the γ-globin genes but rather its chromatin occupancy is solely concentrated at CHD4, encoding the NuRD nucleosome remodeler, itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for ZNF410’s effects on γ-globin repression. Knockout of ZNF410 reduces CHD4 by 60%, enough to substantially de-repress HbF while avoiding the cellular toxicity of complete CHD4 loss. Mice with constitutive deficiency of the homolog Zfp410 are born at expected Mendelian ratios with unremarkable hematology. ZNF410 is dispensable for human hematopoietic engraftment potential and erythroid maturation unlike known HbF repressors. These studies identify a new rational target for HbF induction for the β-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved transcription factor with singular devotion to regulation of a chromatin subcomplex.

THE EFFECT OF ALTERATION OF THYROXINE BINDING CAPACITY ON THE DIALYZABLE AND ABSOLUTE FRACTIONS OF TRIIODOTHYRONINE IN CIRCULATION

1973 ◽  
Vol 72 (2) ◽  
pp. 265-271 ◽  
Author(s):  
J. H. Dussault ◽  
D. A. Fisher ◽  
J. T. Nicoloff ◽  
V. V. Row ◽  
R. Volpe
Keyword(s):  
Correlation Coefficient ◽  
Inverse Relationship ◽  
Binding Capacity ◽  
Hormone Concentration ◽  
Thyroxine Binding Globulin ◽  
Serum Thyroxine ◽  
A Value ◽  
The Mean ◽  
Male Subjects ◽  
Female Subjects

ABSTRACT In order to determine the effect of alterations in binding capacity of thyroxine binding globulin (TBG) on triiodothyronine (T3) metabolism, studies were conducted in 10 patients with idiopathically low (7 subjects) or elevated (3 subjects) TBG levels and 10 subjects given norethandrolone (7 male subjects) or oestrogen (3 female subjects). Measurements of serum thyroxine (T4) concentration, maximal T4 binding capacity, serum T3 concentration and per cent dialyzable T3 were conducted. Serum T3 was measured both by chemical and radioimmunoassay methods. In patients with idiopathically low TBG, the mean serum T4 concentration was low (2.4 μg/100 ml), the mean serum T3 level low (55 ng/100 ml), the mean per cent dialyzable T3 increased (0.52%), and the calculated free T3 concentration normal (186 pg/100 ml). In patients with idiopathically high TBG levels the mean T4 concentration was high (10.3 μg/100 ml), the mean T3 level slightly elevated (127 ng/100 ml), the% dialyzable T3 low (0.10%) and the calculated free T3 concentration low normal (123 pg/100 ml). The correlation coefficient between the per cent dialyzable T3 and maximal TBG binding capacity in the 20 subjects was 0.68, a value significant at the P < 0.01 level. Thus, alterations in binding capacity of TBG seem to influence T3 and T4 metabolism similarly; the inverse relationship between the % of dialyzable hormone and total hormone concentration tends to keep the absolue levels of free hormones stable.

The underrepresentation of female participants in studies assessing the impact of high-dose exercise on cardiovascular outcomes: a scoping review

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
S Pallikadavath ◽  
R Patel ◽  
CL Kemp ◽  
M Hafejee ◽  
N Peckham ◽  
...  
Keyword(s):  
Scoping Review ◽  
High Volume ◽  
Cardiovascular Outcomes ◽  
High Dose ◽  
Funding Sources ◽  
Review Protocol ◽  
The Mean ◽  
The Impact ◽  
Over Time ◽  
Funding Acknowledgements

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Cardiovascular adaptations as a result of exercise conducted at high-intensity and high-volume are often termed the ‘Athlete’s heart’. Studies have shown that these cardiovascular adaptations vary between sexes. It is important that both sexes are well represented in this literature. However, many studies assessing the impact of high-dose exercise on cardiovascular outcomes under-recruit female participants. Purpose This scoping review aimed to evaluate the representation of females in studies assessing the impact of high-dose exercise on cardiovascular outcomes and demonstrate how this has changed over time. Methods The scoping review protocol as outlined by Arksey and O’Malley was used. OVID and EMBASE databases were searched and studies independently reviewed by two reviewers. Studies must have investigated the effects of high-dose exercise on cardiovascular outcomes. To assess how the recruitment of females has changed over time, two methods were used. One, the median study date was used to categorise studies into two groups. Two, studies were divided into deciles to form ten equal groups over the study period. Mean percentage of female recruitment and percentage of studies that failed to include females were calculated. Results Overall, 250 studies were included. Over half the studies (50.8%, n = 127) did not include female participants. Only 3.2% (n = 8) did not include male participants. Overall, mean percentage recruitment was 18.2%. The mean percentage of recruitment was 14.5% before 2011 and 21.8% after 2011. The most recent decile of studies demonstrated the highest mean percentage of female recruitment (29.3%) and lowest number of studies that did not include female participants (26.9%). Conclusion Female participants are significantly underrepresented in studies assessing cardiovascular outcomes caused by high-dose exercise. The most recent studies show that female recruitment may be improving, however, this still falls significantly short for equal representation. Risk factors, progression and management of cardiovascular diseases vary between sexes, hence, translating findings from male dominated data is not appropriate. Future investigators should aim to establish barriers and strategies to optimise fair recruitment. Mean percentage females recruited per study (%) Percentage studies that do not include women (%) Overall (n = 250) 18.2 50.8 (n = 127) Studies before 2011 (n = 121) 14.5 59.5 (n = 72) Studies after 2011 (n = 129) 21.8 42.6 (n = 55) Table 1: Female recruitment characteristics. The year 2011 (median study year) was chosen as this divides all included studies into two equal groups.

scholarly journals Effect of Posterior Tibial Slope Change on Postoperative Range of Motion and Clinical Outcomes after Posterior Cruciate-Substituting Total Knee Arthroplasty

2021 ◽  
Author(s):  
O-Sung Lee ◽  
Jangyun Lee ◽  
Myung Chul Lee ◽  
Hyuk-Soo Han
Keyword(s):  
Total Knee Arthroplasty ◽  
Range Of Motion ◽  
Correlation Coefficient ◽  
Knee Arthroplasty ◽  
Tibial Slope ◽  
Posterior Tibial Slope ◽  
Posterior Tibial ◽  
Clinical Scores ◽  
Total Knee ◽  
The Mean

AbstractThe posterior tibial slope (PTS) is usually adjusted by less than 5 degrees, without considering its individual difference, during posterior cruciate-substituting (PS) total knee arthroplasty (TKA). The effect of these individual changes of PTS would be important because clinical results depending on postoperative PTS were reported conflictingly. We investigated the effect of the change in PTS on the postoperative range of motion (ROM) and clinical scores after PS TKA. We retrospectively reviewed 164 knees from 107 patients who underwent PS TKA with a 2-year follow-up. We analyzed the preoperative and postoperative PTS, ROM, visual analog scale pain scale, Western Ontario and McMaster University Index (WOMAC), Hospital for Special Surgery Knee Score, Knee Society Score, and Forgotten Joint Score (FJS). The association of the absolute change in PTS with ROM and clinical scores was analyzed using correlation analysis and multiple regression analysis. As a result, the mean PTS and mean ROM changed from 9.6 ±  3.4 and 120.1 ±  15.4 degrees preoperatively to 2.0 ±  1.3 and 128.4 ±  9.3 degrees postoperatively, and the mean PTS change was 7.6 ±  3.5 degrees. The PTS change had no statistically significant association with the postoperative ROM and clinical scoring systems, although it did have a weak positive correlation with WOMAC function, No 10 (difficulty in rising from sitting) (correlation coefficient = 0.342, p = 0.041), and moderate positive correlation with the FJS, No. 6 (awareness when climbing stairs) (correlation coefficient = 0.470, p = 0.001). The authors concluded that the amount of change in PTS did not affect the postoperative ROM and clinical scores, although proximal tibial resection with a constant target of PTS resulted in individually different changes in the PTS after PS TKA,

scholarly journals Fetal hemoglobin induction by acetate, a product of butyrate catabolism [see comments]

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3198-3204 ◽  
Author(s):  
G Stamatoyannopoulos ◽  
CA Blau ◽  
B Nakamoto ◽  
B Josephson ◽  
Q Li ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Sickle Cell Disease ◽  
Umbilical Cord Blood ◽  
Sodium Acetate ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Gamma Globin ◽  
Hbf Induction ◽  
Globin Synthesis

Abstract Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates gamma-globin synthesis is unknown. In the course of butyrate catabolism, beta oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in gamma-globin protein and gamma mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of gamma/gamma + beta mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-gamma monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in gamma-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of gamma- chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb mu locus control region (mu LCR) cassette linked to a 3.3-kb A gamma gene displayed a near twofold increase in gamma mRNA during a 10-day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of gamma-globin synthesis, with the percentage of HbF- containing reticulocytes (F reticulocytes) approaching 30%. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two- carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.

Prolactin stimulates food intake in a dose-dependent manner

1989 ◽  
Vol 256 (1) ◽  
pp. R276-R280 ◽  
Author(s):  
T. Gerardo-Gettens ◽  
B. J. Moore ◽  
J. S. Stern ◽  
B. A. Horwitz
Keyword(s):  
Food Intake ◽  
Female Rats ◽  
High Dose ◽  
Dependent Manner ◽  
Additional Control ◽  
The Mean ◽  
Ovine Prolactin ◽  
Dose Dependent ◽  
Medium Dose ◽  
Cumulative Food Intake

Lactation in the rat is marked by pronounced hyperphagia and suppression of brown fat (BAT) thermogenic capacity. We previously examined the possibility that elevated prolactin levels mediate these changes. The present study evaluated the effect of varying prolactin levels on food intake, BAT mitochondrial GDP binding, and carcass adiposity. Female rats were injected daily for 10 days with ovine prolactin at one of three doses: high = 3.0, medium = 1.0, or low = 0.3 micrograms/g body wt. Controls were injected with 0.9% NaCl. A group of uninjected rats served as an additional control. Cumulative food intake was significantly elevated in a dose-dependent manner in the prolactin-treated animals relative to the saline-injected and uninjected controls. Compared with the saline controls, the mean cumulative food intake was greatest at the high dose (20% increase), intermediate at the medium dose (17%), and smallest at the low dose (12%). Prolactin-treated rats gained significantly more weight during the experiment than did controls. Despite the hyperphagia in the prolactin-treated rats, no significant differences in BAT mitochondrial GDP binding were observed among the five groups. These data indicate that elevated prolactin levels stimulate food intake in a dose-dependent manner and that this hyperphagia is not accompanied by an increase in BAT mitochondrial GDP binding.

Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers

1987 ◽  
Vol 17 (4) ◽  
pp. 869-873 ◽  
Author(s):  
C. Schmauss ◽  
J.-C. Krieg
Keyword(s):  
Low Dose ◽  
Matched Control ◽  
Control Group ◽  
High Dose ◽  
Withdrawal Therapy ◽  
The Mean ◽  
Dose Dependent ◽  
Dose Dependent Effect ◽  
Age And Sex

SynopsisIn 17 benzodiazepine (BDZ) dependent in-patients a CT scan was performed before initiation of withdrawal therapy. The evaluation of the ventricular to brain ratio (VBR) by standardized and computerized measurements revealed significantly higher mean VBRs for both high-and low-dose BDZ-dependent patients compared to the mean VBR of an age- and sex-matched control group. In addition, the mean VBR of high-dose BDZ-dependent patients (N = 8) was significantly higher than the mean VBR of low-dose BDZ-dependent patients (N = 9). This difference could not be accounted for by the age of the patients or duration of BDZ-dependency and, therefore, suggests a dose-dependent effect of BDZs on the enlargement of internal CSF-spaces. On the other hand, higher values for the width of external CSF-spaces were found to be related to increasing age of the patients and duration of BDZ-dependency.

scholarly journals High-Dose, Short-Duration, Early Valacyclovir Therapy for Episodic Treatment of Cold Sores: Results of Two Randomized, Placebo-Controlled, Multicenter Studies

2003 ◽  
Vol 47 (3) ◽  
pp. 1072-1080 ◽  
Author(s):  
Spotswood L. Spruance ◽  
Terry M. Jones ◽  
Mark M. Blatter ◽  
Mauricio Vargas-Cortes ◽  
Judy Barber ◽  
...  
Keyword(s):  
Day Treatment ◽  
High Dose ◽  
Herpes Labialis ◽  
Lesion Development ◽  
Multicenter Studies ◽  
Double Blind ◽  
Cold Sore ◽  
Treatment Groups ◽  
The Mean ◽  
Cold Sores

ABSTRACT Oral valacyclovir is better absorbed than oral acyclovir, increasing acyclovir bioavailability three- to fivefold. This provides the opportunity to explore whether high systemic acyclovir concentrations are effective in the treatment of cold sores (herpes labialis). Two randomized, double-blind, placebo-controlled studies were conducted. Subjects were provided with 2 g of valacyclovir twice daily for 1 day (1-day treatment), 2 g of valacyclovir twice daily for 1 day and then 1 g of valacyclovir twice daily for 1 day (2-day treatment), or a matching placebo and instructed to initiate treatment upon the first symptoms of a cold sore. In study 1, the median duration of the episode (primary endpoint) was reduced by 1.0 day (P = 0.001) with 1-day treatment and 0.5 days (P = 0.009) with 2-day treatment compared to placebo. Similarly, the mean duration of the episode was statistically significantly reduced by 1.1 days with 1-day treatment and 0.7 days with 2-day treatment compared to placebo. The proportion of subjects in whom cold sore lesion development was prevented and/or blocked was increased by 6.4% (P = 0.096) with 1-day treatment and 8.5% (P = 0.061) with 2-day treatment compared to placebo. The time to lesion healing and time to cessation of pain and/or discomfort were statistically significantly reduced with valacyclovir compared to placebo. In study 2, results similar to those in study 1 were obtained. AEs were similar across treatment groups. These studies provide evidence supporting a simple, 1-day valacyclovir treatment regimen for cold sores that is safe and effective. The 1-day valacyclovir regimen offers patients a unique and convenient dosing alternative compared to available topical therapies.

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