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.     

Adjustments in daily energy expenditure to caloric restriction and weight loss by adult obese and lean Zucker rats

The 24 h resting (postabsorptive) energy expenditure of adult female lean and obese Zucker rats was examined both at the body weights each genotype spontaneously maintained and at body weights that were reduced 6-10 percent by restricting food intake for 2 weeks to 70 or 55 percent of normal. At their normally-maintained body weight, lean rats expended energy at a daily rate appropriate to their body mass according to the Kleiber equation (predicted kcal/day = 70.0 x BW-0.75kg observed kcal/day = 70.66 x BW-0.75kg). However, expenditure rates declined significantly in the weight-reduced lean rats restricted to 70 or 55 percent of normal intake (to 64.1 and 61.3 kcal/kg0.75). The obese rats expended energy at a rate lower than predicted by the Kleiber equation prior to weight loss (49.5 x BW-0.75kg). But, rates of daily expenditure in the obese rats was further reduced by 70 or 55 percent restriction (to 43.7 and 42.4 x BW-0.75kg), a decline proportionately as large or larger than that displayed by restricted lean rats. With this reduced metabolic rate, the total daily caloric expenditure of obese rats restricted to 55 percent of normal intake approximated that of unrestricted lean rats weighing only half as much (27.8 vs 27.5 kcal/day; 569 vs 285 g). Evidently, Zucker obese rats display the same adaptive reductions in resting metabolism as do leans in response to energy deficit and weight loss. In both, these adjustments in expenditure act to stabilize body weight at the levels that typify each genotype.     

Molecular basis of altered red blood cell membrane properties in Southeast Asian ovalocytosis: role of the mutant band 3 protein in band 3 oligomerization and retention by the membrane skeleton

Southeast Asian ovalocytosis (SAO) is an asymptomatic trait characterized by rigid, poorly deformable red cells that resist invasion by several strains of malaria parasites. The underlying molecular genetic defect involves simple heterozygous state for a mutant band 3 protein, which contains a deletion of amino acids 400 through 408, linked with a Lys 56-to-Glu substitution (band 3-Memphis polymorphism). To elucidate the contribution of the mutant SAO band 3 protein to increased SAO red blood cell (RBC) rigidity, we examined the participation of the mutant SAO band 3 protein in increased band 3 attachment to the skeleton and band 3 oligomerization. We found first that SAO RBC skeletons retained more band 3 than normal cells and that this increased retention preferentially involved the mutant SAO band 3 protein. Second, SAO RBCs contained a higher percentage of band 3 oligomer-ankyrin complexes than normal cells, and these oligomers were preferentially enriched by the mutant SAO protein. At the ultrastructural level, the increased oligomer formation of SAO RBCs was reflected by stacking of band 3-containing intramembrane particles (IMP) into longitudinal strands. The IMP stacking was not reversed by treating SAO RBCs in alkaline pH (pH 11), which is known to weaken ankyrin-band 3 interactions, or by removing the cytoplasmic domain of band 3 from SAO membranes with trypsin. Finally, we found that band 3 protein in intact SAO RBCs exhibited a markedly decreased rotational mobility, presumably reflecting the increased oligomerization and the membrane skeletal association of the SAO band 3 protein. We propose that the mutant SAO band 3 has an increased propensity to form oligomers, which appear as longitudinal strands of IMP and exhibit increased association with membrane skeleton. This band 3 oligomerization underlies the increase in membrane rigidity by precluding membrane skeletal extension, which is necessary for membrane deformation.     

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.     

Student support in accelerated nursing programs: Gender-based perspectives and impact on academic outcomes

Background

Factors that contribute to student success in accelerated degree nursing programs are poorly understood and may vary by gender.

Central and regional hemodynamic effects and neurohumoral consequences of minoxidil in severe congestive heart failure and comparison to hydralazine and nitroprusside

Minoxidil is a potent oral vasodilator of potential value in patients with congestive heart failure (CHF), although preliminary studies show that it causes fluid retention. To test whether minoxidil acts primarily as an arterial vasodilator in CHF, it was compared with hydralazine and nitroprusside. To evaluate its chronic efficacy and mechanism of fluid retention, the effects of minoxidil (7 patients) were compared, in a double-blind manner, with those of hydralazine (8 patients) on central and regional hemodynamics and the renin-angiotensin-aldosterone and sympathetic nervous systems. There was no demonstrable difference in the central hemodynamic effects of minoxidil and hydralazine in the dosages used. After 6 hours both drugs increased cardiac index (minoxidil group, from 1.65 ± 0.29 to 2.26 ± 0.40 liters /min/m², p < 0.0001; hydralazine group, from 1.88 ± 0.61 to 2.34 ± 0.90 liters/min/m², p < 0.0001), decreased systemic vascular resistance and increased heart rate without change in pulmonary arterial, pulmonary capillary wedge or right atrial pressures. Nitroprusside effects differed from those of minoxidil and hydralazine with respect to heart rate (p < 0.005) and mean pulmonary arterial (p < 0.007) and right atrial (p < 0.009) pressures. Nitroprusside also decreased relative hepatomesenteric flow compared with the other 2 agents (p < 0.005). Neither renal blood flow, glomerular filtration rate, filtration fraction, nor urinary sodium excretion were significantly altered acutely by any of the 3 drugs. Minoxidil and hydralazine did not differ in their neurohumoral effects: Both agents produced an increase in plasma norepinephrine concentration (p < 0.003) and plasma renin activity (p < 0.04), but no change in plasma epinephrine or aldosterone concentrations. After 1 week of double-blind therapy, fluid retention was a greater problem with minoxidil than with hydralazine. Thus, minoxidil behaves primarily as an arterial vasodilator in CHF, fluid retention is a severe adverse effect, and the greater degree of fluid retention with minoxidil than hydralazine is not attributable to differing acute effects on total renal blood flow or function, or differing effects on the renin-angiotensin-aldosterone or sympathetic nervous systems.     

Recurrent hemoperitoneum in women receiving continuous ambulatory peritoneal dialysis

Of 27 women in the reproductive age group receiving continuous ambulatory peritoneal dialysis for more than 3 months, 4 of 7 who menstruated developed recurrent hemoperitoneum. Tubal ligation had been done in 3 of these 4 women. There were 37 episodes of hemoperitoneum; 22 occurred at midcycle and 15 with menstruation. One patient required repeated blood transfusion, but after oral anovulant therapy no further bleeding occurred and no transfusion was required. Two patients needed laparotomy: one for heavy intraperitoneal bleeding originating from a luteal cyst, and the other for severe lower abdominal pain from follicular and luteal cysts. Ultrasound examinations suggested the presence of small ovarian cysts in the two remaining patients. Recurrent midcycle hemoperitoneum in women on continuous ambulatory peritoneal dialysis may be triggered by ovulation and associated ovarian cyst formation. Suppression of ovulation should be considered.     

Practical management of patients with painful diabetic neuropathy

PURPOSE: Painful diabetic neuropathy (PDN) has a significant impact on patients' quality of life, affecting sleep, mood, mobility, ability to work, interpersonal relationships, overall self-worth, and independence. The purpose of this article is to provide diabetes educators with current and essential tools for PDN assessment and management. METHODS: Medline and CINAHL database searches identified publications on the assessment and treatment of PDN. Identified research was evaluated, and information pertinent to diabetes educators was summarized. RESULTS: Recent advancements in assessment of neuropathic pain include identifying characteristics that distinguish between neuropathic and nonneuropathic pain. In the absence of treatment, research demonstrates that nerve damage may progress while pain diminishes. Many disease-modifying and symptom-management treatment options are available. CONCLUSION: Good glycemic control is the first priority for both prevention and management of PDN. However, even with good glycemic control, up to 20% of patients will develop PDN. PDN recognition and assessment are critical to optimize management. Although several treatment modalities are available, few patients obtain complete pain relief. Recent advances in understanding the mechanisms underlying neuropathic pain should lead to better treatment and patient outcomes. Combination therapy, including nonpharmacologic modalities, may be required. Research evaluating the efficacy of combination therapy is needed.