Granulocyte colony-stimulating factor administration to healthy volunteers: analysis of the immediate activating effects on circulating neutrophils

In four healthy volunteers, we analyzed in detail the immediate in vivo effects on circulating neutrophils of subcutaneous administration of 300 micrograms of granulocyte colony-stimulating factor (G-CSF). Neutrophil activation was assessed by measurement of degranulation. Mobilization of secretory vesicles was shown by a decrease in leukocyte alkaline phosphatase content of the circulating neutrophils. Furthermore, shortly postinjection, Fc gamma RIII was found to be upregulated from an intracellular pool that we identified by immunoelectron microscopy as secretory vesicles. Intravascular release of specific granules was shown by increased plasma levels of lactoferrin and by upregulation of the expression of CD66b and CD11b on circulating neutrophils. Moreover, measurement of fourfold elevated plasma levels of elastase, bound to its physiologic inhibitor alpha 1- antitrypsin, indicated mobilization of azurophil granules. However, no expression of CD63, a marker of azurophil granules, was observed on circulating neutrophils. G-CSF--induced mobilization of secretory vesicles and specific granules could be mimicked in whole blood cultures in vitro, in contrast to release of azurophil granules. Therefore, we postulate that the most activated neutrophils leave the circulation, as observed shortly postinjection, and undergo subsequent stimulation in the endothelial microenvironment, resulting in mobilization of azurophil granules. Our data demonstrate that G-CSF should be regarded as a potent immediate activator of neutrophils in vivo.     

Associations between the leptin receptor gene and adiposity in middle-aged Caucasian males from the HERITAGE family study

Linkage and association studies between three exonic polymorphisms in the leptin receptor gene and body composition variables in the HERITAGE Family Study were undertaken. Polymorphisms K109R, Q223R, and K656N have been analyzed with body mass index (BMI), sum of height skinfolds (SF8), fat mass (FM), percent body fat (%FAT), fat free mass, and plasma leptin level. Single-point linkage analysis and covariance analysis across genotypes were performed, by race, on phenotypes adjusted for age and sex. Blacks (88 parents; 231 adult offspring) from 115 nuclear families (72-119 sibpairs) and Caucasians (192 parents; 330 adult offspring) from 99 nuclear families (319-364 sibpairs) were used for these analyses. In Caucasians, BMI and FM showed suggestive linkages with K109R (P = 0.02 and P = 0.05, respectively) and associations with Q223R (P = 0.005 and P = 0.03, respectively). In blacks, no statistically significant linkage or association was observed. In Caucasians, associations with Q223R were observed in parents, but not in offspring, for BMI, FM, and %FAT (0.04< or =P< or =0.0001). Males, not females, showed differences across genotypes for the same phenotypes plus SF8 and leptin (0.03< or = P< or =0.0002). Carriers of the R223 allele showed higher values than noncarriers for BMI (+4 U, P = 0.0001), SF8 (+30 mm, P = 0.01), FM (+7 kg, P = 0.0004), %FAT (+5%, P = 0.0002), and leptin (+4 ng/mL, P = 0.0006). These results indicate a significant effect of leptin receptor on adiposity in middle-aged Caucasian males.     

Review: Head and neck squamous cell carcinoma in sub-Saharan Africa

Aim

Review the literature from 1990 to 2013 to determine known anatomic sites, risk factors, treatments, and outcomes of head and neck squamous cell carcinoma (HNSCC) in sub-Saharan Africa.

Methods

Using a systematic search strategy, literature pertaining to HNSCC in sub-Saharan Africa was reviewed and patient demographics, anatomic sites, histology, stage, treatment, and outcomes were abstracted. The contributions of human immunodeficiency virus (HIV), human papillomavirus (HPV) and behavioural risk factors to HNSCC in the region were assessed.

Results

Of the 342 papers identified, 46 were utilized for review, including 8611 patients. In sub-Saharan Africa, the oropharyngeal/oral cavity was found to be the most common site, with 7750 cases (90% of all cases). Few papers distinguished oropharyngeal from oral cavity, making identification of possible HPV-associated oropharyngeal squamous cell carcinoma (SCC) difficult. SCC of the nasopharynx, nasal cavity, or paranasal sinuses was identified in 410 patients (4.8% of all cases). Laryngeal SCC was found in 385 patients (4.5% of all cases), and only 66 patients (0.8% of all cases) with hypopharyngeal SCC were identified. In 862 patients with data available, 43% used tobacco and 42% used alcohol, and reported use varied widely and was more common in laryngeal SCC than that of the oropharyngeal/oral cavity. Toombak and kola nut use was reported to be higher in patients with HNSCC. Several papers reported HIV-positive patients with HNSCC, but it was not possible to determine HNSCC prevalence in HIV-positive compared to negative patients. Reports of treatment and outcomes were rare.

Conclusions

The oropharyngeal/oral cavity was by far the most commonly reported site of HNSCC reported in sub-Saharan Africa. The roles of risk factors in HNSCC incidence in sub-Saharan Africa were difficult to delineate from the available studies, but a majority of patients did not use tobacco and alcohol.     

Interactions among the beta2- and beta3- adrenergic receptor genes and total body fat and abdominal fat level in the HERITAGE Family Study

OBJECTIVE AND SUBJECTS: Interactions between markers in the beta2- and beta3-adrenergic receptor (ADR) genes and total body fat and computerized tomography-measured abdominal fat phenotypes were studied in the HERITAGE Family Study cohort of Black (n=205; 81 males and 124 females) and White (n=415; 198 males and 217 females) subjects before and after an endurance training program. RESULTS: In Black subjects, beta2- and beta3-ADR gene variants showed evidence of interactions on changes in total body fat mass and abdominal fat area (P<0.005 and =0.010, respectively). Black subjects who were carriers of both beta2-ADR Arg16 and beta3-ADR Arg64 alleles had a greater decrease in total fat mass as well as abdominal total and subcutaneous, but not visceral fat areas in response to endurance training than subjects with other genotype combinations (P from 0.011 to 0.047). After correction for multiple tests, the findings remained essentially unchanged for total body fat mass and abdominal fat area, but became nonsignificant for subcutaneous fat area. The changes in abdominal fat correlated positively with the changes in fat mass (P<0.0001). The interactions between beta2 and beta3-ADR gene markers accounted for a maximum of 3% of the variances in the response of total fat mass and abdominal fat area to endurance training in Black subjects but it was not significant in White subjects. CONCLUSION: Interactions between sequence variants in the beta2-beta3-ADR gene contributed to the changes in fat mass and abdominal adiposity in response to endurance training in Black subjects.     

Polymorphisms of the beta2-adrenergic receptor gene (ADRB2) in relation to cardiovascular risk factors in men

OBJECTIVE: To investigate the effect of polymorphisms in codon 16 (Arg16Gly) and codon 27 (Gln27Glu) of the beta2-adrenergic receptor gene (ADRB2) on anthropometric, endocrine, metabolic and haemodynamic variables. DESIGN: A cross-sectional study. SUBJECTS: A subgroup of 284 Swedish men from a population sample of 1040 at the age of 51 years. MAIN OUTCOME MEASURES: Genotype examination of ADRB2 polymorphisms in codon 16 and codon 27 with polymerase chain reaction and restriction fragment length polymorphism. Anthropometric measurements included body mass index, waist-to-hip ratio and abdominal sagittal diameter. Endocrine measurements included blood levels of testosterone, insulin-like growth factor I, and leptin plus salivary cortisol. Overnight fasting values of serum insulin, blood glucose, triglycerides, total, low and high density lipoprotein cholesterol, as well as blood pressure and resting heart rate, were also determined. RESULTS: Polymorphisms were frequent in both codon 16 and codon 27. The Arg16Gly genotype showed significant relationships to elevated central distribution of body fat and to systolic blood pressure, whilst the Glu27Glu genotype was associated with elevated leptin and triglyceride levels but not to other measurements, including obesity variables. CONCLUSIONS: We conclude that only a few cardiovascular risk factors are associated with DNA sequence variation in the ADRB2 in Swedish men.     

Heterogeneous glycaemic and insulinaemic responses to oral glucose in non-diabetic men: interactions between duration of obesity,body fat distribution and family history of diabetes mellitus

Summary The interaction between environmental and genetic factors in the alterations of glucose-insulin homeostasis was studied in 104 non-diabetic men. Family history of diabetes mellitus was used as an index of genetic predisposition to diabetes. Body composition was measured by under-water weighing whereas subcutaneous and visceral adipose tissue areas were measured at the abdominal and femoral levels by computed tomography. The sample was first divided into two groups. The first group included subjects with normal glycaemic and insulinaemic responses during a 75 g oral glucose tolerance test. The second group was composed of subjects either with a high glucose response or high insulin response or both. Men included in the second group were different from the normal subjects for almost all body fatness variables. They also presented a prevalence of a positive family history of diabetes which was significantly higher than normal subjects. The second group was then divided into three distinct subgroups based on insulin and glucose responses of the subjects during the oral glucose tolerance test. Subjects with high insulin but normal glucose responses were characterized by significantly higher levels of total body fat and deep abdominal adipose tissue when compared to the normal group (p<0.05). Men with both high insulinaemic and glycaemic responses displayed higher body fatness values and higher deep and subcutaneous abdominal adipose tissue areas (p<0.05) in comparison with normal subjects. They also had a higher body mass index at age 20 years than control subjects and subjects with high insulin but normal glucose responses. In contrast, subjects with normal insulin but with high glucose responses were not different from the normal group with regard to body fat and adipose tissue areas. These results show the heterogeneous origin of altered glucose-insulin homeostasis in non-diabetic men. Finally, subjects in the altered glucose-insulin homeostasis group with no family history of diabetes displayed a higher body mass index at age 20 years (p<0.05) in comparison with subjects who had a positive family history of the disease. They also presented a greater abdominal-to-thigh fat ratio measured by computed tomography. These results suggest that in men with alterations of glucose-insulin homeostasis, the relationship of body fat distribution to glucose tolerance and plasma insulin levels is different in those with no family history of diabetes than in subjects with a positive family history of diabetes.     

Correlates of plasma very-low-density lipoprotein concentration and composition in premenopausal women

Potential correlates of plasma very-low-density lipoprotein (VLDL) concentration and composition were studied in a sample of 75 premenopausal women. Fasting plasma free fatty acid (FFA) levels, as well as plasma glucose and insulin levels in the fasting state and during an oral glucose tolerance test, displayed significant positive correlations with plasma triglyceride (TG) and VLDL-TG levels (P less than .005). Plasma post-heparin lipoprotein lipase (LPL) activity, measured in a subsample of 31 women from the original sample, was negatively correlated with plasma TG, VLDL-cholesterol (CHOL), VLDL-TG, and VLDL-apolipoprotein (apo) B concentrations (.005 greater than P less than .05). Multivariate analyses showed that, after LPL was considered, the insulin area was the only other metabolic variable studied that was significantly correlated with VLDL-apo B concentration, whereas fasting FFA levels were significantly correlated with plasma TG and VLDL-TG levels. ANOVA revealed that plasma VLDL-CHOL, VLDL-TG, and VLDL-apo B levels were not associated with the glucose area, but were significantly associated with the insulin area (P less than .005). When the effect of insulin area was controlled for, the plasma FFA levels did not contribute significantly to the variance in VLDL-CHOL and VLDL-apo B, but showed an independent effect on VLDL-TG levels (P less than .05). Finally, stepwise multiple regression analyses indicated that once the variance explained by plasma LPL activity and by the insulin area was considered, no other metabolic variable could account for the variation in VLDL-CHOL and VLDL-apo B levels, whereas fasting FFA levels explained a further 5% of the VLDL-TG variance and one third of the variance observed in the VLDL-TG/apo B ratio.(ABSTRACT TRUNCATED AT 250 WORDS)