Effects of erythropoietin treatment on cell-mediated immune responses in predialysis patients

OBJECTIVE: The effects of erythropoietin (EPO) treatment on the immune functions of dialysis patients have been shown to be controversial and there are only limited data concerning predialysis patients. MATERIAL AND METHODS: Twenty-four predialysis patients with renal anemia were assigned to subcutaneous EPO treatment, and those in need (n=19) were additionally treated with i.v. iron every other week. We analyzed the effect of the start of EPO treatment on (i) lymphocyte and lymphocyte subclass counts, (ii) lymphocyte stimulation functions and (iii) persisting IgG-class antibody levels to the viral antigens of Epstein-Barr virus and cytomegalovirus. RESULTS: Our main findings were a decrease in the absolute lymphocyte count, combined with decreases in all the main lymphocyte subclass counts. The absolute number of cells with activation and memory markers remained constant, and therefore their proportion slightly increased. The proliferation responses to phytohemagglutinin, tuberculin and tetanus declined significantly, while the amount of IgG-class viral antibodies remained unchanged, meaning that the humoral side of immunity was not affected by the start of the EPO treatment. Similarly, the proliferation response to pokeweed mitogen, a B-cell mitogen, was unchanged. CONCLUSIONS: EPO treatment has a suppressive effect on cellular immune functions of predialysis patients. This suppression does not correlate with erythropoiesis, kidney function or iron status.     

Influence of the rate of temperature change on thermal thresholds in man

Thermal thresholds (cool, warm, heat, heat pain) were determined in four skin regions (cheek, glabrous skin of the hand, hairy forearm, leg) of eight healthy human subjects. The thermostimulator was composed of Peltier elements and three rates of continuous stimulation were used: 1.4, 2.4, and 3.9 degrees C/s. Warm, heat, and heat pain thresholds increased with increasing rate of temperature change, and the increase was of equal magnitude with these three thresholds. However, the effect of increasing stimulus rate on cool thresholds was nonsignificant. Similar results were obtained in all skin regions studied. It is suggested that liminal warm, heat, and heat pain sensations are mediated by afferent fibers with conduction velocities of the same range (C-fibers) whereas liminal cool sensations are signaled by faster conducting afferent fibers.     

Autoregulation of LH/hCG Receptors and Catabolism of hCG in Rat Testis

The number of free and occupied LH/hCG-receptors in adult rat testes after subcutaneous injections of hCG was studied. When 3–10 IU of hCG was injected, there was initially (between 6 and 16 h) a significant increase in free binding sites, without detectable occupancy of receptors. Higher doses (100 and 1000 IU) induced a drop in the amount of free receptors which was explained by simultaneous receptor occupancy. Later (between 12 and 48 h) there was a pronounced net loss of both free and occupied binding sites. Gel filtration of radioactivity extracted from testicular tissue demonstrated that following the initial uptake [¹²⁵I]hCG undergoes a cleavage to subunits and hydrolysis to peptide fragments and amino acids. The autoradiographic results suggest that the degradative processes take place in Leydig cells. The degradation of [¹²⁵I]hCG was markedly reduced by simultaneous injection of an excess of unlabelled hormone, supporting the autoradiographic evidence of the degradation site of [¹²⁵I]hCG.     

Arteriomegaly

The features of a patient with arteriomegaly of thoracic and abdominal aorta, common and external iliac, and femoral arteries are described.     

Placebo-controlled double-blind trial of pirprofen and an ergotamine tartrate compound in migraine attacks

Sixty-one patients, 16 with classic and 45 with common migraine, were treated during three subsequent attacks with pirprofen, a new inhibitor of prostaglandin synthesis; an ergotamine tartrate compound; or placebo, in a randomized, double-blind multicentre study. Pain relief after a single dose and reduction of the attack intensity occurred most often with pirprofen in patients who needed more than one dose. Among them, however, the duration of attack was shortest with ergotamine. Working ability was well preserved with pirprofen, especially among patients with common migraine, and this treatment was ranked highest by the patients. However, no statistically significant differences were found between pirprofen and ergotamine. No serious side effects were observed with pirprofen. This study establishes the usefulness of pirprofen in the treatment of acute migraine.     

Effects of exercise intensity and duration on nocturnal heart rate variability and sleep quality

Acute physical exercise may affect cardiac autonomic modulation hours or even days during the recovery phase. Although sleep is an essential recovery period, the information on nocturnal autonomic modulation indicated by heart rate variability (HRV) after different exercises is mostly lacking. Therefore, this study investigated the effects of exercise intensity and duration on nocturnal HR, HRV, HR, and HRV-based relaxation, as well as on actigraphic and subjective sleep quality. Fourteen healthy male subjects (age 36 ± 4 years, maximal oxygen uptake 49 ± 4 ml/kg/min) performed five different running exercises on separate occasions starting at 6 p.m. with HR guidance at home. The effect of intensity was studied with 30 min of exercises at intensities corresponding to HR level at 45% (easy), 60% (moderate) and 75% (vigorous) of their maximal oxygen uptake. The effect of duration was studied with 30, 60, and 90 min of moderate exercises. Increased exercise intensity elevated nocturnal HR compared to control day (p < 0.001), but it did not affect nocturnal HRV. Nocturnal HR was greater after the day with 90- than 30- or 60-min exercises (p < 0.01) or control day (p < 0.001). Nocturnal HRV was lower after the 90-min exercise day compared to control day (p < 0.01). Neither exercise intensity nor duration had any impact on actigraphic or subjective sleep quality. The results suggest that increased exercise intensity and/or duration cause delayed recovery of nocturnal cardiac autonomic modulation, although long exercise duration was needed to induce changes in nocturnal HRV. Increased exercise intensity or duration does not seem to disrupt sleep quality.     

Increased plasma membrane expression of human follicle-stimulating hormone receptor by a small molecule thienopyr(im)idine

A thienopyr(im)idine (Org41841) activates the luteinizing hormone (LH) receptor but does not compete with the natural ligand binding site and does not show agonistic action on the follicle-stimulating hormone receptor (hFSHR) at sub-millimolar concentrations. When this drug is preincubated at sub-micromolar concentrations with host cells expressing the hFSHR, and then washed out, binding analysis and assessment of receptor-effector coupling show that it increases plasma membrane expression of the hFSHR. Real-time PCR shows that this effect did not result from increased hFSHR mRNA accumulation. It is possible that Org41841 behaves as a pharmacoperone, a drug which increases the percentage of newly synthesized receptor routing to the membrane. Like pharmacoperones for other receptors, this drug was able to rescue a particular mutant hFSHR (A(189)V) associated with misrouting and endoplasmic reticulum retention, although other mutants could not be rescued. This is potentially the first member of the pharmacoperone drug class which binds at a site that is distinctive from the ligand binding site.     

Depression and smoking across 25 years of the Normative Aging Study

OBJECTIVE: The majority of past findings indicate that smokers are more likely than non-smokers to report depressive symptoms and that depression may act as an impediment to smoking cessation. The aim of the present study is to examine the stability of the relationship between depressive symptoms and smoking status and to determine whether the presence of depressive symptoms predicts continued smoking. METHODS: Subjects were initially healthy men (n = 2208) from the Veterans Administration Normative Aging Study, an ongoing cohort of older men who have been re-assessed every 3-5 years for a period of 25 years. Depressive symptoms measures employed were the Cornell Medical Index, the MMPI-2 Content Depression Scale, and the Center for Epidemiological Studies Depression Scale. RESULTS: Depression scores were higher among continuing smokers compared to never and former smokers and those who quit after entering the study. None of the three depressive symptoms measures were associated with decreased likelihood of smoking cessation. The change in MMPI-2 depression scores observed in a 4-year follow-up was the same among those who quit and those who remained smokers. CONCLUSIONS: Higher prevalence of depressive symptoms among male smokers is stable across time and is likely to contribute to higher morbidity and mortality among these smokers. However, presence of depressive symptoms did not have a significant impact on smoking cessation.     

CVID-associated TACI mutations affect autoreactive B cell selection and activation

Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptor superfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cell activation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7 and TLR9 and plays an important role during B cell activation and the central removal of autoreactive B cells in healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune tolerance and secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B cell lymphoma 6–expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance, whereas residual B cell responsiveness in patients with one, but not two, TACI mutations enables autoimmune complications.