Abstract: ABSTRACT: INTRODUCTION: Many approaches have been examined to try to predict patient outcome after cardiopulmonary resuscitation. It has been shown that plasma DNA could predict mortality in critically ill patients but no data are available regarding its clinical value in patients after out-of-hospital cardiac arrest. In this study we investigated whether plasma DNA on arrival at the emergency room may be useful in predicting the outcome of these patients. METHODS: We performed a prospective study of out-of-hospital patients with cardiac arrest who achieved return of spontaneous circulation after successful resuscitation. Cardiovascular co-morbidities and resuscitation history were recorded according to the Utstein Style. The outcome measures were 24 h and overall in-hospital mortality. Cell-free plasma DNA was measured by real-time quantitative PCR assay for the -globin gene in blood samples drawn within 2 hours after the arrest. Descriptive statistics, multiple logistic regression analysis, and receiver operator characteristic (ROC) curves were calculated. RESULTS: 85 consecutive patients were analyzed with a median time to return of spontaneous circulation of 27 min [interquartile range (IQR) 18-35]. Thirty patients died within 24-h and 58 died during the hospital course. Plasma DNA concentrations at admission were higher in non-survivors at 24 h than in survivors (median 5520 genome equivalents (GE)/ml, vs 2810 GE/ml, P < 0.01), and were also higher in patients who died in the hospital than in survivors to discharge (median 4150 GE/ml vs 2460 GE/ml, P < 0.01). Lactate clearance at 6 h was significantly higher in 24 h survivors (P < 0.05). The area under the ROC curves for plasma DNA to predict 24-h mortality and in-hospital mortality were 0.796 (95 % confidence interval (CI) 0.701- 0.890) and 0.652 (95 % CI 0.533-0.770). The best cut-off value of plasma DNA for 24-h mortality was 4340 GE/ml (sensitivity 76 %, specificity 83 %), and for in-hospital mortality was 3485 GE/ml (sensitivity 63 %, specificity 69 %). Multiple logistic regression analysis showed that the risk of 24-h and of in-hospital mortality increased 1.75-fold and 1.36-fold respectively, for every 500 GE/ml increase in plasma DNA. CONCLUSIONS: Plasma DNA levels may be a useful biomarker in predicting outcome after out-of hospital cardiac arrest.
Abstract: Monocyte exposure to LPS induces a transient state in which these cells are refractory to further endotoxin stimulation. This phenomenon, termed endotoxin tolerance (ET), is characterized by a decreased production of cytokines in response to the proinflammatory stimulus. We have established a robust model of ET and have determined the time frame and features of LPS unresponsiveness in cultured human monocytes. A large number of genes transcribed in tolerant monocytes were classified as either "tolerizable" or "nontolerizable" depending on their expression levels during the ET phase. Tolerant monocytes exhibit rapid IL-1R-associated kinase-M (IRAK-M) overexpression, high levels of triggering receptor expressed on myeloid cells-1 (TREM-1) and CD64, and a marked down-regulation of MHC molecules and NF-kappaB2. These cells combine potent phagocytic activity with impaired capability for Ag presentation. We also show that circulating monocytes isolated from cystic fibrosis patients share all the determinants that characterize cells locked in an ET state. These findings identify a new mechanism that contributes to impaired inflammation in cystic fibrosis patients despite a high frequency of infections. Our results indicate that a tolerant phenotype interferes with timing, efficiency, and outcome of the innate immune responses against bacterial infections.
Abstract: PURPOSE: A comparison of the topographic astigmatism generated after coaxial phacoemulsification (CP) through temporal 2.8 mm incision and biaxial phacoemulsification (MICS) through superior-oblique trapezoidal 1.5-2 mm incisions. SETTING: Centre for Visual Sciences (Instituto de Ciencias Visuales, INCIVI), Madrid, SpainMethods This prospective randomized clinical study included 94 eyes of 64 patients; 43 eyes were operated on through CP and 51 through MICS. Corneal topography was measured before operation, and subsequently after 1, 3, and 6 months. Additionally, a control group (C) of 55 eyes was created (performing two topographies on them); the change in astigmatism was calculated without having performed any surgical procedure. The astigmatic change in the three groups was measured through arithmetic, polar and vector analysis (Alpins method). RESULTS: In the vector analysis, results after the first month following surgery were: mean module of the surgically induced astigmatism (SIA) 0.49+/-0.38 D in CP and 0.48+/-0.37 D in MICS, while 0.31+/-0.27 D in group C. Although no statistically significant differences were detected between the two surgical techniques, differences were noted when comparing group C with each of these techniques (P<0.05). The distribution of the SIA axes showed a slight tendency to be located more frequently at around 90 degrees in CP, and at around 50 degrees in MICS. CONCLUSIONS: The mean module of SIA was similar in CP and in MICS, although the distribution of the direction of such a vector revealed minor differences.
Abstract: The effects of diet supplementation with the antioxidant vitamin E (200 mg daily) on several blood neutrophil, lymphocyte and natural killer cell functions have been investigated in healthy elderly men and women before supplementation, after 3 months of supplementation and 6 months after the end of supplementation (post-supplementation). In parallel, samples of healthy adult men and women were used as age controls. In elderly men and women, an impairment of immune functions was observed in comparison with the respective adult controls and the intake of vitamin E resulted in a significant enhancement of immune parameters in both elderly men and women, bringing their values close to those in the adults. These effects were not found in post-supplementation samples in several but not in all functions. The present findings suggest that supplementation with vitamin E can produce an improvement of immune functions and therefore of health in aged people.
Abstract: Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene that codes for the chloride channel, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CF patients are frequently colonized by several pathogens, but the mechanisms that allow colonization in spite of apparently functional immune systems are incompletely understood. In this paper we show that blood peripheral monocytes isolated from CF patients are found in an endotoxin tolerance state, yet this is not due to a deficient TLR activation. On the other hand, levels of the amplifier of inflammatory responses, TREM-1 (Triggering Receptor Expressed on Myeloid cells), are notably down-regulated in monocytes from patients, in comparison to those extracted from healthy volunteers. Furthermore, the soluble form of TREM-1 (sTREM-1) was not detected in the sera of patients. Additionally, and in strict contrast to patients who suffer from Chronic Obstructive Pulmonary Disease (COPD), CF monocytes challenged ex vivo with LPS neither up-regulated membrane-anchored TREM-1 nor sTREM-1. Finally, similar levels of PGE(2) expression and p65 translocation into the nucleus were found in both patients and healthy volunteers, thus suggesting that TREM-1 regulation is neither controlled by PGE(2) levels nor by p65 activation in this case. However, PU.1 translocation into the nucleus was significantly higher in CF monocytes than in controls, suggesting a role for this transcription factor in the control of TREM-1 expression. We conclude that down-regulation of TREM-1 expression in cystic fibrosis patients is at least partly responsible for the endotoxin tolerance state in which their monocytes are locked.
Abstract: Acute coronary syndrome (ACS) groups different cardiac diseases whose development is associated with inflammation. Here we have analyzed the levels of inflammatory cytokines and of members of the TLR/IRAK pathway including IRAK-M in monocytes from ACS patients classified as either UA (unstable angina), STEMI (ST-elevation myocardial infarction) or NSTEMI (non-ST-elevation myocardial infarction). Circulating monocytes from all patients, but not from healthy individuals, showed high levels of pro-inflammatory cytokines, TNF-alpha and IL-6, as well as of IRAK-M and IL-10. TLR4 was also up-regulated, but IRAK-1, IRAK-4 and MyD88 levels were similar in patients and controls. Further, we investigated the consequences of cytokines/IRAK-M expression on the innate immune response to endotoxin. Ex vivo responses to LPS were markedly attenuated in patient monocytes compared to controls. Control monocytes cultured for 6 h in supplemented medium (10% serum from ACS patients) expressed IRAK-M, and LPS stimulation failed to induce TNF-alpha and IL-6 in these cultures. Pre-incubation of the serum with a blocking anti-TNF-alpha antibody reduced this endotoxin tolerance effect, suggesting that TNF-alpha controls this phenomenon, at least partially. We show for the first time that inflammatory responses associated with ACS induce an unresponsiveness state to endotoxin challenge in circulating monocytes, which correlates with expression of IRAK-M, TLR4 and IL-10. The magnitude of this response varies according to the clinical condition (UA, STEMI or NSTEMI), and is regulated by TNF-alpha.
Abstract: Osteoclasts are large, multinucleated cells, which originate from the fusion of macrophages. They play a central role in bone development and remodeling via the resorption of bone and are thus important mediators of bone loss, which leads to osteoporosis. IL-1R-associated kinase (IRAK)-M is a pseudokinase, which acts as a negative modulator of innate immune responses mediated by TLRs and IL-1R. Recently, it has been reported that IRAK-M also participates in the control of macrophage differentiation into osteoclasts. In addition, it was shown that IRAK-M knockout mice develop a strong osteoporosis phenotype, suggesting that down-regulation of this molecule activates osteoclast-mediated bone resorption. We studied the effect of the osteoporosis-inducing glucocorticoid, 6-methylprednisolone (6-MP), on IRAK-M expression in osteoclasts. Our results showed that osteoclasts, derived from THP-1 and RAW cells as well as human blood monocytes, differentiated into osteoclasts, express high levels of IRAK-M at mRNA and protein levels. In addition, 6-MP down-regulates IRAK-M expression, which correlates with an increased activation of bone resorption. These findings suggest a mechanism of corticosteroid-induced osteoporosis and open new avenues for treating this endemic disease of Western societies.
Abstract: Triggering receptors expressed on myeloid cell (TREM) proteins are a family of cell surface receptors that participate in diverse cellular processes such as inflammation, coagulation, and bone homeostasis. TREM-1, in particular, is expressed on neutrophils and monocytes and is a potent amplifier of inflammatory responses. LPS and other microbial products induce up-regulation of cell surface-localized TREM-1 and the release of its soluble form, sTREM-1. Two hypotheses have been advanced to explain the origin of sTREM-1: alternative splicing of TREM-1 mRNA and proteolytic cleavage(s) of mature, membrane-anchored TREM-1. In this report, we present conclusive evidence in favor of the proteolytic mechanism of sTREM-1 generation. No alternative splicing forms of TREM-1 were detected in monocytes/macrophages. Besides, metalloproteinase inhibitors increased the stability of TREM-1 at the cell surface while significantly reducing sTREM-1 release in cultures of LPS-challenged human monocytes and neutrophils. We conclude that metalloproteinases are responsible for shedding of the TREM-1 ectodomain through proteolytic cleavage of its long juxtamembrane linker.
Abstract: Although the complex and multifactorial process of tumour growth has been extensively studied for decades, our understanding of the fundamental relationship between tumour growth dynamics and genetic expression profile remains incomplete. Recent studies of tumour dynamics indicate that gene expression in solid tumours would depend on the distance from the centre of the tumour. Since tumour proliferative activity is mainly localised to its external zone, and taking into account that generation and expansion of genetic mutations depend on the number of cell divisions, important differences in gene expression between central and peripheral sections of the same tumour are to be expected. Here, we have studied variations in the genetic expression profile between peripheral and internal samples of the same brain tumour. We have carried out microarray analysis of mRNA expression, and found a differential profile of genetic expression between the two cell subsets. In particular, one major nuclear protein that regulates cell responses to DNA-damaging and stress signals, GADD45alpha, was expressed at much lower levels in the peripheral zone, as compared to tumour core samples. These differences in GADD45alpha mRNA transcription levels have been confirmed by quantitative analysis via real time PCR, and protein levels of GADD45alpha also exhibit the same pattern of differential expression. Our findings suggest that GADD45alpha might play a major role in the regulation of brain tumour invasive potential.
Abstract: PURPOSE OF REVIEW: The pseudo-kinase interleukin-1 receptor-associated kinase-M has emerged as a critical molecule in the down-regulation of inflammatory responses. Dysregulation of the toll-like receptor-interleukin-1 receptor-associated kinase system, and in particular interleukin-1 receptor-associated kinase-M up-regulation, are associated with a number of pathologies. This review highlights recent findings on interleukin-1 receptor-associated kinase-M reported in biomedical literature. RECENT FINDINGS: Interleukin-1 receptor-associated kinase-M plays a critical role in generating a refractory state of the immune system following monocytes/macrophages encounter with bacteria or tumor cells. This state has been demonstrated so far in patients who suffer from sepsis, leukemia, and acute coronary syndrome, and seems to be associated with interleukin-1 receptor-associated kinase-M overexpression in their circulating monocytes. In addition, the pseudo-kinase represents a central regulator of osteoclast differentiation and activation, and might thus be related to the onset of osteoporosis. SUMMARY: Interleukin-1 receptor-associated kinase-M is involved in the control of endotoxin tolerance in monocytes, in osteoporosis, as well as in the deactivation of tumor-infiltrating macrophages. Additionally, patients who suffer from several pathologies related to inflammatory responses express high levels of this molecule in their circulating monocytes. Human monocytes treated with a nitric oxide donor also express large amounts of interleukin-1 receptor-associated kinase-M, apparently under the control of tumor necrosis factor-alpha. This mechanism could explain the induction of interleukin-1 receptor-associated kinase-M in monocytes from patients who suffer from an inflammatory pathology.
Abstract: Sepsis-associated encephalopathy (SAE) is a frequent but poorly understood neurological complication in sepsis that negatively influences survival. Here we present clinical and experimental evidence that this brain dysfunction may be related to altered neurotransmission produced by inflammatory mediators. Compared with septic patients, SAE patients had higher interleukin-1beta (IL-1beta) plasma levels; interestingly, these levels decreased once the encephalopathy was resolved. A putative IL-1beta effect on type A gamma-aminobutyric acid receptors (GABA(A)Rs), which mediate fast synaptic transmission in most cerebral inhibitory synapses in mammals, was investigated in cultured hippocampal neurons and in Xenopus oocytes expressing native or foreign rat brain GABA(A)Rs, respectively. Confocal images in both cell types revealed that IL-1beta increases recruitment of GABA(A)Rs to the cell surface. Moreover, brief applications of IL-1beta to voltage-clamped oocytes yielded a delayed potentiation of the GABA-elicited chloride currents (I(GABA)); this effect was suppressed by IL-1ra, the natural IL-1 receptor (IL-1RI) antagonist. Western blot analysis combined with I(GABA) recording and confocal images of GABA(A) Rs in oocytes showed that IL-1beta stimulates the IL-1RI-dependent phosphatidylinositol 3-kinase activation and the consequent facilitation of phospho-Akt-mediated insertion of GABA(A)Rs into the cell surface. The interruption of this signaling pathway by specific phosphatidylinositol 3-kinase or Akt inhibitors suppresses the cytokine-mediated effects on GABA(A)R, whereas activation of the conditionally active form of Akt1 (myr-Akt1.ER*) with 4-hydroxytamoxifen reproduces the effects. These findings point to a previously unrecognized signaling pathway that connects IL-1beta with increased "GABAergic tone." We propose that through this mechanism IL-1beta might alter synaptic strength at central GABAergic synapses and so contribute to the cognitive dysfunction observed in SAE.
Abstract: In contrast to the thoroughly characterized mechanisms of positive regulation within cytokine signaling pathways, our knowledge of negative feedback loops is comparatively sparse. We and others have previously reported that IRAK-M down-regulates inflammatory responses to multiple stimuli. In particular, we could show that the nitric oxide (NO) donor, GSNO, induces IRAK-M overexpression in human monocytes. Here we study the expression of another important negative regulator of cytokine signaling, SOCS-1, in human monocytes exposed to GSNO. The NO donor induced significant levels of SOCS-1 mRNA and protein, 6 h and 16 h after stimulation, respectively. Monocytes stimulated with GSNO for longer periods (24 h and 48 h) failed to express IL-6 and IP-10 upon LPS challenge. In addition, and in line with previous reports of NO-mediated induction of TNF-alpha, we have found that exposure to this cytokine induces SOCS-1 mRNA in human monocytes. A blocking antibody against TNF-alpha impaired SOCS-1 expression upon GSNO treatment and re-instated IL-6 and IP-10 mRNA levels after LPS challenge in cultures pretreated with the NO donor. We conclude that NO stimulates SOCS-1 overexpression in a pathway at least partially regulated by TNF-alpha.
Abstract: Although blood monocytes possess significant cytotoxic activity against tumor cells, tumor-infiltrating monocytes are commonly deactivated in cancer patients. Monocytes pre-exposed to tumor cells show significantly decreased expression levels of TNF-alpha, IL-12p40, and IL-1R-associated kinase (IRAK)-1. Activation of the Ser/Thr kinase IRAK-1 is an important event in several inflammatory processes. By contrast, another IRAK family member, IRAK-M, negatively regulates this pathway, and is up-regulated in cultures of endotoxin-tolerant monocytes and in monocytes from septic patients within the timeframe of tolerance. In this study, we show that IRAK-M expression is enhanced at the mRNA and protein level in human monocytes cultured in the presence of tumor cells. IRAK-M was induced in monocytes upon coculturing with different tumor cells, as well as by fixed tumor cells and medium supplemented with the supernatant from tumor cell cultures. Moreover, blood monocytes from patients with chronic myeloid leukemia and patients with metastasis also overexpressed IRAK-M. Low concentrations of hyaluronan, a cell surface glycosaminoglycan released by tumor cells, also up-regulated IRAK-M. The induction of IRAK-M by hyaluronan and tumor cells was abolished by incubation with anti-CD44 or anti-TLR4 blocking Abs. Furthermore, down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates both TNF-alpha mRNA expression and protein production in human monocytes re-exposed to a tumor cell line. Altogether, our findings indicate that deactivation of human monocytes in the presence of tumor cells involves IRAK-M up-regulation, and this effect appears to be mediated by hyaluronan through the engagement of CD44 and TLR4.
Abstract: The activation of interleukin receptor associated kinases (IRAK) is an important event in several inflammatory processes. However, exposing monocytes to a nitric oxide (NO) donor inhibits the activity of IRAK-1 and its molecular interaction with TNF receptor associated factor-6 (TRAF6). Despite the fact that NO is known to regulate many events in the immune and vascular system, the mechanism that underlies this inhibition remains unknown. We have recently demonstrated that IRAK-M inhibits the TLR/IRAK pathway during endotoxin tolerance and thus, we hypothesized that IRAK-M may be involved in the inhibition of IRAK-1 activity in the presence of NO. Hence, we have analyzed the expression of IRAK-M in human monocytes following exposure to a NO donor (GSNO) and we have observed that GSNO was capable of inducing IRAK-M mRNA and protein expression 8 and 20 h after stimulation, respectively. It is known that NO induces the expression of TNF-alpha in monocytes and we found that exposure to TNF-alpha induced IRAK-M mRNA expression in human monocytes within 2 h of stimulation. Furthermore, the expression of IRAK-M induced by GSNO was inhibited by the presence of a blocking antibody raised against TNF-alpha. Thus, our data indicate that stimulation of human monocytes with a NO donor results in a clear induction of IRAK-M and this is dependent on the release of TNF-alpha by this kind of cells.
Abstract: Several genes coding for different cytokines may affect host susceptibility to tuberculosis. This study investigates the relationship of the single base change polymorphic variants identified in the first intron of interferon-gamma (+874 T/A) and in the promoter region of interleukin-10 gene (-1,082 G/A), with cytokine production by peripheral blood mononuclear cells and tuberculosis susceptibility. We studied a Spanish population of 113 patients with culture-proven pulmonary tuberculosis, 207 healthy close contacts (125 tuberculin reactive and 82 tuberculin negative), and 100 healthy tuberculin-negative control subjects. Multiple logistic regression analysis showed that individuals homozygous for the interferon-gamma (+874) A allele had a 3.75-fold increased risk of developing tuberculosis (95% confidence interval, 2.26-6.23, p = 0.0017). Stimulated production of interferon-gamma by peripheral mononuclear cells from patients with genotype AA was depressed compared with that of non-AA homozygotes at the time of diagnosis and after completion of therapy. Multivariate analysis showed that the presence of an AA genotype and the absolute number of lymphocytes were the only independent predictors of interferon-gamma production. In contrast, the different rates of interleukin-10 production associated with the interleukin-10 polymorphism did not affect susceptibility to tuberculosis. Thus, a genetic defect in the production of interferon-gamma in individuals homozygous for the (+874) A allele could contribute to their increased risk of developing tuberculosis.
Abstract: The exposure of human monocytes to the gram-negative endotoxin LPS provokes them to enter a transient state in which they are refractory to further stimulation by LPS. This phenomenon is known as 'endotoxin tolerance' (ET) and it is characterized by a decrease in leukocyte proinflammatory cytokine production in response to LPS. In the present study, we have analyzed the expression of IRAK-M mRNA and protein in a human model of ET using human monocytes isolated from peripheral blood. In these monocyte cultures, IRAK-M mRNA was expressed 6h after stimulation with different doses of LPS. However, endotoxin pretreatment induced a more immediate up-regulation of IRAK-M gene expression, transcripts appearing only one hour after a second LPS-challenge, and the production of high levels of IRAK-M protein in these tolerant monocytes. We also analyzed the response of monocytes isolated from septic patients within a temporal tolerance timeframe when stimulated ex vivo with LPS. In contrast to monocytes from healthy volunteers and patients outside of the tolerance timeframe, monocytes from septic patients rapidly expressed IRAK-M mRNA when stimulated with LPS ex vivo. Moreover, the expression of IRAK-M mRNA was more rapidly induced in the presence of a PI3K inhibitor, suggesting a connection between these two kinases. Thus, our data indicate that IRAK-M could play a pivotal role in the process of ET in human monocytes and provide evidence that PI3K is involved in regulating its expression.
Abstract: This study aims to determine the influence of the polymorphism within the intron 2 of the interleukin-1 receptor antagonist gene (IL-1RN*) on the outcome of severe sepsis, and to assess its functional significance by correlating this polymorphism with the total production of interleukin-1 receptor antagonist (IL-1Ra) protein determined in stimulated peripheral blood mononuclear cells (PBMC). A group of 78 patients with severe sepsis (51 survivors and 27 nonsurvivors) was compared with a healthy control group of 130 blood donors, and 56 patients with uncomplicated pneumonia. We found a significant association between IL-1RN* polymorphism and survival. Thus, after adjusting for age and APACHE II score, multiple logistic regression analysis showed that patients homozygotes for the allele *2 had a 6.47-fold increased risk of death (95% CI 1.01--41.47, P = 0.04). Besides, compared with patients homozygous or heterozygous for the allele *1, IL-1RN*2 homozygotes produced significantly lower levels of IL-1Ra from their PBMC. Our results suggest that insufficient production of this cytokine might contribute, among other factors, to the higher mortality rate found in severe sepsis patients with the IL-1RN*2 homozygous genotype.
Abstract: Fever of unknown origin (FUO) associated with HIV infection is different from classic FUO. Relevant etiologies, procedures and time to diagnosis were analyzed. Patients admitted with FUO from 1991 to 1996 were prospectively followed. Thirty with classic FUO (group I) and 46 with FUO and HIV (group II) were included. Data on diagnosis, time to achieve it, and procedures were registered. Diagnosis was obtained in 87% and 93% of cases in groups I and II. Infections were the most frequent cause in group II. Collagen diseases were found in group I and absent in group II. Prevalence of neoplasia was similar. Mean time to diagnosis was near 5 weeks. In HIV the predominant diagnostic method was the Lowenstein culture. Invasive methods were similarly employed. It is concluded that predominance of Mycobacteria and absence of collagen diseases make FUO associated with HIV a different form of FUO. No differences were found in approach and time to diagnosis.
Abstract: Diabetes mellitus may be associated with intracellular glutathione (GSH) deficiency. Since in vivo studies have shown that plasma intracellular GSH plays a key role in regulating the activation of nuclear factor kappaB (NF-kappaB), we have investigated the relationship between intracellular thiols (GSH, homocysteine, cysteine and cysteinyglycine) and NF-kappaB activity in the peripheral blood mononuclear cells (PBMC) of 63 elderly non-insulin dependent diabetes mellitus (NIDDM) patients (28 microalbuminurics and 35 normoalbuminurics) and 30 healthy age- and sex-matched subjects. In addition, we have measured plasma concentrations of these thiol compounds, serum concentrations of interleukin-6 (IL-6) and vascular cell adhesion molecule-1 (sVCAM-1), that are partly dependent on the NF-kappaB activation, as well as the serum levels of thiobarbituric acid reacting substances (TBARS), as index of lipid peroxidation. Diabetic patients with microalbuminuria (MAB) and normoalbuminuria had NF-kappaB activity 2.1- and 1.5-fold greater, respectively, than the control group. As compared to normoalbuminuric patients, patients with MAB had significantly higher levels of glycemia, plasma homocysteine, and serum concentrations of TBARS, IL-6 and sVCAM-1 (in all cases, p < 0.01), and significantly lower GSH content in the PBMC (p < 0.05). The intracellular GSH in PBMC correlated with NF-kappaB activation (r = -0.82; p < 0.0001), serum TBARS (r = -0.60; p < 0.001), and with fasting glycemia (r = -0.56; p < 0.001) in patients with MAB, whereas a weaker association between GSH levels in PBMC and NF-kappaB activation (r = -0.504, p < 0.001) was seen in patients without MAB. These results suggest that the decrease of intracellular GSH content in elderly NIDDM patients with MAB is strongly associated with enhanced NF-kappaB activation, which could contribute to the development of increased glomerular capillary permeability and its rapid progression.
Abstract: The relationship between fluctuating cytokine concentrations in plasma and the outcome of sepsis is complex. We postulated that early measurement of the activation of nuclear factor kappaB (NF-kappaB), a transcriptional regulatory protein involved in proinflammatory cytokine expression, may help to predict the outcome of sepsis. We determined NF-kappaB activation in peripheral blood mononuclear cells of 34 patients with severe sepsis (23 survivors and 11 nonsurvivors) and serial concentrations of inflammatory cytokines (interleukin-6, interleukin-1, and tumor necrosis factor) and various endogenous antagonists in plasma. NF-kappaB activity was significantly higher in nonsurvivors and correlated strongly with the severity of illness (APACHE II score), although neither was related to the cytokine levels. Apart from NF-kappaB activity, the interleukin-1 receptor antagonist was the only cytokine tested whose level in plasma was of value in predicting mortality by logistic regression analysis. These results underscore the prognostic value of early measurement of NF-kappaB activity in patients with severe sepsis.
Abstract: Incubation of bovine adrenal chromaffin cells in high K+ (38 mM) during 24-48 h enhanced 2.5 to five times the expression of SNAP-25 protein and mRNA, respectively. This increase was reduced 86% by furnidipine (an L-type Ca2+ channel blocker) but was unaffected by either omega-conotoxin GVIA (an N-type Ca2+ channel blocker) or -agatoxin IVA (a P/Q-type Ca2+ channel blocker). Combined blockade of N and P/Q channels with omega-conotoxin MVIIC did, however, block by 76% the protein expression. The inhibitory effects of fumidipine were partially reversed when the external Ca2+ concentration was raised from 1.6 to 5 mM. These findings, together with the fact that nicotinic receptor activation or Ca2+ release from internal stores also enhanced SNAP-25 protein expression, suggest that an increment of cytosolic Ca2+ concentration ([Ca2+]), rather than its source or Ca2+ entry pathway, is the critical signal to induce the protein expression. The greater coupling between L-type Ca2+ channels and protein expression might be due to two facts: (a) L channels contributed 50% to the global [Ca2+]i rise induced by 38 mM K+ in indo-1-loaded chromaffin cells and (b) L channels undergo less inactivation than N or P/Q channels on sustained stimulation of these cells.
Abstract: Since moderate hyperhomocysteinemia is an independent risk factor for vascular disease by mean of its oxidant effect and glutathione plays a main role as intracellular redox-regulating agent, we have studied for the first time the total intracellular content of homocysteine in aging. Plasma homocysteine concentration, total intracellular and plasma glutathione, and other related thiol compounds such as cysteine and the glutathione catabolite cysteinglycine were also studied. Forty three healthy elderly subjects and twenty seven healthy young ones were studied. The total intracellular peripheral blood mononuclear cell content was higher for homocysteine, cysteine and cysteinglycine, whereas that of the total glutathione was greatly decreased in elderly people with respect to young ones. Elderly subjects showed significantly higher levels than young ones of total plasma homocysteine and cysteinglycine, but not cysteine, whereas total plasma glutathione levels were increased. In addition, elderly subjects showed significantly decreased plasma vitamin E levels and increased concentrations of serum lipid peroxides measured as TBARS (reaction product of malondialdehyde with thiobarbituric acid). The intracellular glutathione content presented significantly negative correlation with serum TBARS, and intracellular and plasma homocysteine levels. These findings show an increase of homocysteine synthesis associated with aging, which in turn can produce an augmented oxidant effect on endothelium, and an impaired intracellular antioxidant capacity leading to an enhanced lipid peroxidation and decreased total intracellular glutathione content.
Abstract: OBJECTIVE: To test whether oxidative stress could promote a systemic acute-phase response in elderly patients with type II diabetes. DESIGN AND METHODS: In a group of 30 older diabetic patients with poor glycemic control, serum levels of lipid peroxides, measured as thiobarbituric acid-reacting substances (TBARS); C-reactive protein (CRP); interleukin (IL)-6 and the soluble form of its receptor (slL-6R), were evaluated at baseline and after 2 and 3 months of therapeutic intervention. Thirty asymptomatic, untreated individuals with abnormal fasting glycemia, but otherwise healthy status, of similar age, sex, and weight served as control group. RESULTS: At baseline, glycemia (8.83 +/- 0.67mmol/l), HbA1C (8.66 +/- 0.59%), TBARS (8.68 +/- 1.21 micromol/l), CRP (16.05 +/- 3.81 mg/l) IL-6 (5.39 +/- 1.25 pg/ml) and sIL-6R (1425 +/- 492 pg/ml) were significantly higher in diabetic patients than in asymptomatic hyperglycemic individuals (p<0.001). After treatment, glycemia significantly decreased with respect to baseline values (- 9.82% after 60 days and -13.74% after 90 days), as did serum levels of TBARS (-14.05% and -21.89%, respectively), CRP (-32.71% and -43.86%), IL-6 (-23.75% and -40.63%) and sIL-6R (-34.53% and -48.49%, respectively). In diabetic patients, multiple regression showed, at each time, that TBARS and IL-6 were independently correlated with CRP, considering CRP as the dependent variable. Similar correlations were found in asymptomatic hyperglycemic subjects. CONCLUSION: These results suggest that oxidative stress might be implicated in promoting a state of low-grade systemic inflammation in elderly patients with type II diabetes.
Abstract: Leptin production is increased in rodents by administration of endotoxin or cytokines. To investigate whether circulating leptin is related to cytokine release and survival in human sepsis, plasma concentrations of leptin, interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, soluble TNF receptor type I, IL-1 receptor antagonist (IL-1ra), and the inflammatory modulator IL-10 were measured as soon as severe sepsis (n=28) or septic shock (n=14) developed and every 6 h for 24 h. Patients with sepsis or septic shock had leptin concentrations 2.3- and 4.2-fold greater, respectively, than the control group. There was an independent association for leptin with IL-1ra and IL-10 in both patient groups. By discriminant analysis, leptin and IL-6 were independent predictors of death. These findings suggest that increases in leptin levels may be a host defense mechanism during sepsis.
Abstract: Cytokines are a group of hormone-like polypeptides that play a variety of regulatory roles in host defense against infection. Because of the possible different involvement of these mediators in bacterial infections and tuberculosis, enzyme immunoassay was used to measure comparatively the plasma levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and interferon gamma (IFN-gamma) in 25 immunocompetent patients divided into two groups: in 12 patients clinical and microbiological diagnosis showed a chronic bacterial infection and 13 patients had pleuropulmonar tuberculosis. After resolution of the infectious disorders (> or = 3 months), these measurements were repeated for each patient. High levels of IL-1b, TNF-alpha and IL-6 were observed at study entry, but no significant difference was found between the groups. In contrast, plasma levels (mean +/- SEM) of IFN-gamma were significantly higher in patients with tuberculosis when compared with the bacterial group (0.753 +/- 0.201 vs 0.325 +/- 0.105 IU/ml; P = 0.020). This different pattern of plasma proinflammatory cytokines could be ascribed to a prevaling role of the mediators of so-called Th-1 immune response (IFN-gamma) in host defense against infection with Mycobacterium tuberculosis.
Abstract: Abdominal pain in patients with chronic pancreatitis has been related to an increase in plasma cholecystokinin (CCK) levels. The aim of the study was to disclose the relation of the altered response with the low intraduodenal bile acids levels found in these patients. Twenty patients with chronic pancreatitis were classified into groups I (n = 11) and II (n = 9) according to the presence or absence of pain. Intraduodenal trypsin and bile acids concentrations and plasma CCK levels were measured before and 30, 60, and 90 min after a test meal. Comparisons between values in both groups were carried out. Correlation of intraduodenal trypsin and bile acids with plasma CCK was analyzed. Patients with pain exhibited significantly lower intraduodenal trypsin levels at 30 and 90 min and lower basal and postprandial intraduodenal bile acids levels than patients without pain. In patients with pain, basal and postprandial plasma CCK levels were significantly higher than in patients without pain. A negative correlation was demonstrated between intraduodenal bile acids and plasma CCK. In patients with chronic pancreatitis and pain, a reduction in intraduodenal postprandial trypsin and basal and postprandial bile acids concentrations, as well as an increase in basal and postprandial plasma CCK levels, was encountered. A negative correlation between intraduodenal bile acids and plasma CCK concentrations was detected that may be implicated in the pathogenesis of pain.
Abstract: OBJECTIVE: To examine the relation of circulating appetite neuropeptides, CCK-8 sulphate (CCK-8s) and beta-endorphin, and the tumour necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNFR) to the anorexia and wasting associated with HIV-infection. DESIGN: Cross-sectional analysis. SETTING: A university-based HIV/AIDS ambulatory clinic in Madrid, Spain. PARTICIPANTS: Thirty-six randomly selected AIDS patients without concomitant diseases or secondary infections were classified into two groups: 19 patients with wasting and 17 with normal body weight, and 18 healthy controls. MEASUREMENTS: Nutritional status was evaluated by anthropometry, laboratory parameters and self-report of appetite. Plasma levels of TNF-alpha and sTNFR proteins p55 (sTNFR-p55) and p75 (sTNFR-p75) were determined by enzyme immunoassay, whereas CCK-8s and beta-endorphin levels were measured by radioimmunoassay. RESULTS: AIDS patients with wasting had significantly higher plasma concentrations of CCK-8s, but lower levels of beta-endorphin when compared to well-nourished AIDS patients (P < 0.01) or controls (P < 0.001). Mean levels of TNF-alpha, and sTNFR-p55 and sTNFR-p75 were greater in AIDS patients with wasting than in asymptomatic AIDS patients or in controls. No significant association was observed between any of these circulating peptides and the parameters of malnutrition. CONCLUSIONS: An activation of the TNF system, together with reciprocal changes in plasma concentrations of two neuropeptides with opposing appetite regulation, that is increased concentrations of CCK-8s but lower levels of beta-endorphin, are associated with the presence of HIV wasting. We hypothesize that these changes may contribute to the development of HIV wasting by producing a pathological inhibition of appetite.
Abstract: BACKGROUND: The ascertainment of patients who consume important amounts of alcohol admitted to a hospital is essential to prevent medical and psychological complications. Carbohydrate deficient transferrin (CDT) is a new marker of alcohol consumption which requires validation in the hospital setting. METHODS: The values of carbohydrate deficient transferrin (CDT), glutamic oxalacetic transaminase (GOT), gamma glutamil transpeptidase (GGT) and mean corpuscular volume (MCV) were measured in 101 consecutive patients admitted to the Internal Medicine and Surgery Departments. Considering amounts higher than 60 g/day of ethanol for male patients and higher than 40 g/day for female patients as risk consumption, the values for sensitivity, specificity and area under the curve were calculated for the different biological tests. RESULTS: Twenty-six percent of patients reported a consumption of risk. The sensitivity of the tests were lower than 50% and specificities higher than 77%. CDT had the lowest sensitivity (15%) but it was very specific (98%). CDT had a better sensitivity among women than among men. None of the tests had an area under the curve with adequate efficiency levels. CONCLUSIONS: CDT among the hospitalized patients and other biological markers of alcohol consumption have a low efficiency.
Abstract: This study is aimed to investigate the relationship between plasma concentrations of nitrite and nitrate as a measure of ongoing nitric oxide (NO) production, the vasodilatory neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP), endotoxemia and hemodynamic changes in human septic shock. Thirteen patients with septic shock were studied within 6 h after the development of hypotension. Hemodynamic measurements and blood samples were recorded simultaneously at 2-h intervals from study admission. Eighteen normotensive patients with sepsis were included as control group of patients. On study entry, circulating levels of endotoxin did not relate to either CGRP or nitrite and nitrate plasma values. Septic shock patients had significantly higher plasma CGRP, and nitrite and nitrate concentrations, at each of the four time points, than patients with sepsis, as well as both groups of patients compared to normal subjects. No differences were found in plasma SP levels between the two groups of patients. For pooled data from all septic shock patients and measurements (n = 52), both plasma concentrations of CGRP and nitrite and nitrate were inversely correlated, independently from each other, to systemic vascular resistance. On study admission and at 2-h intervals, plasma CGRP concentrations correlated directly with nitrite and nitrate values. Our observations, thus, point to CGRP acting in concert with NO as important mediators responsible for hypotension in human septic shock.
Abstract: OBJECTIVE: To study GIP and insulin release after a test meal in patients with chronic pancreatitis with and without secondary diabetes mellitus. METHODS: 28 patients with chronic pancreatitis were classified in groups I and II according to the presence or absence of secondary diabetes mellitus. Twelve healthy subjects were included as controls. After a test meal plasma GIP levels and serum insulin levels were determined at 0, 30, 60, 120 and 180 min. RESULTS: A significant diminished GIP response was found in the groups of patients with respect to the control group. No association could be detected with severity of pancreatic insufficiency. Higher values of GIP were demonstrated at 60 and 120 min in patients without diabetes than in patients with it. CONCLUSIONS: An abnormal GIP response is present in cases of chronic pancreatitis irrespective of the presence or severity of pancreatic insufficiency. This response is further affected if secondary diabetes mellitus is present.
Abstract: In the present study, we have investigated the effect in vitro of gastrin-releasing peptide (GRP, 10(-10) M), neuropeptide Y (NPY, 10(-10) M), somatostatin (10(-10) M) and vasoactive intestinal peptide (VIP, 10(-9) M) on the production of IL-1 beta, IL-6 and TNF alpha by peripheral whole blood cells from healthy young and old people. We have found that GRP, NPY, somatostatin and VIP stimulated the production of IL-1 beta in old subjects, and NPY, somatostatin and VIP in young ones. In addition, the production of IL-6 was enhanced by GRP, NPY and VIP in young and old people. The TNF alpha production was stimulated by NPY and somatostatin in young subjects, and by NPY, somatostatin and VIP in old ones, whereas GRP produced a decrease of TNF alpha in young persons. GRP in old subjects and VIP in young and old subjects stimulated in a great degree the LPS-induced IL-6 production by whole blood cells. On the contrary, GRP and VIP inhibited highly the LPS-induced TNF alpha production in young controls. Our results show that these neuropeptides, when added to whole blood cells at physiological concentrations, are able to stimulate the production of IL-1 beta, IL-6 and TNF alpha in a differential way according to the subject age.
Abstract: The aim of this work was to study the hypothesis that the release of vasoactive neuropeptides may be related to the hemodynamic changes and severity of disease in human sepsis and septic shock. Twenty-two patients diagnosed with sepsis and treated in medical wards with standard supportive therapy and twenty patients admitted to a medical intensive care unit because of septic shock were studied Twenty healthy volunteers in a similar age range were enrolled as control group. Blood samples were taken at onset and every 12 hours on the following day after hospital admission to measure plasma concentrations of calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and substance P (SP). Clinical and biochemical variables were measured simultaneously. The Acute Physiology and Chronic Health Evaluation (APACHE) II score was calculated on admission. From the day of admission, septic shock patients had significantly higher plasma CGRP-like immunoreactivity levels than patients with sepsis, as well as both groups of patients compared to control subjects. Plasma NPY-like immunoreactivity levels in patients with either sepsis or septic shock was significantly increased, and plasma SP-like immunoreactivity levels significantly reduced compared to those in controls. Plasma CGRP levels at study entry correlated with the APACHE II score (r = 0.71, p < 0.01), as well as with the cardiac index (r = 0.61, p < 0.05) and systemic vascular resistance index (r = -0.62, p < 0.05). Our data suggest that both CGRP and NPY, but not SP, are increasedly released into the circulation during the development of human sepsis and septic shock. In patients with sepsis the vasoconstriction mediated by the release of NPY appears to counterbalance the vasodilatory effect of CGRP. In septic shock patients, however, the release of NPY might be inadequately low to overcome the widespread CGRP-induced vasodilation.
Abstract: We present the case of a 23 year old patient with Kawasaki syndrome which resolved without sequelae after salicylate treatment. An peculiar finding was that of typical symptoms and signs of bilateral sacroiliitis demonstrated by symmetrically increased articular uptake of technetium 99 diphosphonate. This sacroiliitis disappeared completely after resolution of the syndrome. HLA-B27 ag was negative. Articular affection in Kawasaki syndrome comprises pain and/or swelling of large and small peripheral joints. Acute sacroiliitis is a finding not previously described. We believe this to have been an isolated episode and not the onset of a chronic seronegative spondylarthritis.
Abstract: Plasma and synovial fluid concentrations of interleukin-6 (IL-6), using an enzyme-linked immunosorbent assay, as well as immunoreactive levels of calcitonin gene-related peptide (CGRP), substance P and vasoactive intestinal peptide (VIP) were measured in 18 patients with rheumatoid arthritis and 20 with osteoarthritis of the knee. The concentrations of IL-6 were elevated in both plasma and synovial fluids from patients with rheumatoid arthritis whereas higher levels of substance P-, CGRP- and VIP-like immunoreactivities were found in the synovial fluid, but not in plasma, from patients with rheumatoid arthritis when compared with those in osteoarthritis. Furthermore, IL-6 and substance P levels in synovial fluid were significantly correlated both in rheumatoid arthritis and osteoarthritis patients. Our data seem to support the idea of an important role shared by neuropeptides and IL-6 in the pathogenesis of human inflammatory joint disease.
Abstract: The effect of gold salt therapy on substance P immunoreactivity levels in plasma and synovial fluid was studied in 42 patients with rheumatoid arthritis. Decreased levels of synovial fluid substance P, although not statistically significant, were found in rheumatoid patients who were currently receiving gold therapy when compared to either those patients previously treated or to those who never received this therapy. In addition, we found that patients who received more than 1000 mg of gold salts had significantly lower levels of substance P in synovial fluid than those treated with lower doses. Our results, therefore, seem to support the hypothesis that gold salts appear to be slow-acting neurotoxic drugs that significantly decrease the intrasynovial concentrations of substance P, a well-known inflammatory neuropeptide, in arthritis patients.
Abstract: Some aspects of humoral and cell-mediated immunity and the capacity of peripheral blood mononuclear cells (PBMCs) of fourteen elderly persons with idiopathic anorexia to produce several cytokines, such as tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interleukin-6 and interferon-gamma (IFN gamma), were studied and the results were compared with those obtained in a control group of ten age-matched, normal weight healthy subjects. In addition, spontaneous and induced production of these cytokines was also measured in cultures of PBMCs of fourteen healthy young individuals as a control group of age. A significant decrease in CD2 (pan T-cells) and CD4 (T-helper) lymphocyte subpopulations, but unchanged CD8 (T-suppressor) subset, and a reduced response in delayed cutaneous hypersensitivity tests were observed in senile underweight anorectic patients. Monocyte counts did not show significant differences between patients and control subjects. The spontaneous release by PBMCs of all the cytokines measured did not differ between the anorectic and either the elderly or young control group. A significant increase in IL-6 production after mitogen stimulation with tetradecanoylphorbol acetate (TPA) and phytohemagglutinin (PHA) after 24 and 48 h of culture, as well as a greater induced TNF alpha production after 48 h of incubation with the same mitogens, was found in the anorectic patients as compared with the elderly controls. However, stimulated production of both IL-1 beta with TPA and of IFN gamma with PHA did not differ significantly between anorectics and aged controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: To study the possible role of several amino acids on feeding in the anorexia of aging, we have measured plasma and cerebrospinal fluid (CSF) concentrations of 22 amino acids in 14 elderly persons with idiopathic anorexia and 10 healthy subjects with normal weight in a similar age range. Plasma and CSF amino acid concentrations and CSF homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels were all measured by HPLC methods. Elderly anorectic subjects had significantly lower levels of glutamic acid but increased concentrations of glutamine in both plasma and CSF compared to controls. Likewise, a significant increase of histidine, threonine, alanine, arginine, valine, methionine, isoleucine, leucine, phenylalanine, tryptophan, ornithine and lysine was found in CSF, but not in plasma, from patients with anorexia. Besides, the CSF histidine/LNAA (large neutral amino acids) and tryptophan/LNAA ratios were elevated in anorectic patients as compared with controls of similar age. In addition, we found higher CSF concentrations of HVA and 5-HIAA, as well as a positive correlation between CSF LNAA and either HVA (r = 0.74, p = 0.002) or 5-HIAA (r = 0.61, p = 0.020) concentrations in elderly anorectics. CSF tryptophan correlated positively with 5-HIAA levels (r = 0.59, p = 0.026) and CSF tyrosine with HVA levels (r = 0.77, p = 0.002). Our results suggest that changes in the CSF concentration of amino acids could contribute to an increased biogenic amine metabolism in the central nervous system of elderly anorectic subjects, possibly increasing the synaptic liberation of biogenic amines involved in the appetite regulation.
Abstract: Immunoreactive plasma and synovial fluid concentrations of calcitonin gene-related peptide II (CGRP II), substance P and vasoactive intestinal peptide (VIP) were measured in patients with osteoarthritis, gout and rheumatoid arthritis. Significantly higher levels of CGRP II and substance P-like immunoreactivity levels in synovial fluid were found in gout as well as CGRP II, substance P and VIP-like immunoreactivities in rheumatoid arthritis when compared to those in osteoarthritis. Plasma CGRP II, substance P and VIP-like immunoreactivity levels showed no significant differences among patients in the three different groups of arthritis. Our results suggest that these neuropeptides released from peripheral nerve endings into the synovial cavity probably play a pathogenic role in human joint inflammation.
Abstract: Plasma and cerebrospinal fluid (CSF) concentrations of three well-known satiety neuropeptides, cholecystokinin (CCK), somatostatin and calcitonin gene-related peptide (CGRP), along with two powerful orexigenic neuropeptides, neuropeptide Y (NPY) and beta-endorphin have been measured in elderly persons with idiopathic anorexia and normal weight healthy subjects in a similar age range. Plasma and CSF immunoreactivity levels of the two main fractions of CCK (CCK8s and CCK33) after being separated by HPLC were measured by a radioimmunoassay (RIA) developed in our laboratory, whereas the other neuropeptides were assayed by commercially available RIA kits. Elderly underweight anorectic patients had significantly lower levels of beta-endorphin but increased concentrations of NPY in both plasma and CSF when compared to controls. In addition to significantly higher levels of CCK8s but not CCK33 in plasma, we found a trend to higher CSF concentrations of CCK8s and a positive correlation between the body mass index and either beta-endorphin (r = 0.58, P < 0.05) or CCK8s (r = 0.69, P < 0.01) concentrations in CSF in the anorectic group. CSF somatostatin concentrations were decreased significantly, but plasma somatostatin levels and plasma and CSF concentrations of CGRP were similar in senile anorectics and controls. Treatment of five anorectic patients with megestrol acetate, 480 mg daily for 6 months, reversed only the decrease in CSF beta-endorphin levels but did not normalize the body weight or the fat body mass. On the basis of our findings, we hypothesize that a decrease in CSF beta-endorphin concentration along with a rise in plasma levels of CCK8s might be accounted for the primary anorexia of aging.
Abstract: Plasma and cerebrospinal fluid (CSF) concentrations of two well-known satiety cytokine peptides have been measured in elderly persons with idiopathic anorexia and normal weight healthy subjects in a similar age range. Plasma and CSF levels of tumor necrosis factor alfa (TNF alpha) and interleukin-1 beta (IL-1 beta) were assayed by commercially available kits. Elderly under-weight anorectic patients had significantly lower levels of TNF alpha but unchanged concentrations of IL-1 beta in both plasma and CSF when compared to controls. In addition to significantly lower levels of TNF alpha in CSF, we found a positive correlation between the body mass index and CSF TNF alpha concentrations (r = 0.61, P < 0.05) in the anorectic group. CSF IL-1 beta concentrations showed a significant negative correlation with plasma albumin levels in senile anorectics (r = -0.66, P < 0.05) but not in controls. On the basis of our findings, we conclude that a decrease in plasma and CSF TNF alpha concentrations could have beneficial effects for the primary anorexia of aging both at central level to offset anorexia and at peripheral sites decreasing tissue catabolism.
Abstract: We have performed a longitudinal study of the hypothalamic-pituitary-ovary axis and adrenal function during the menstrual cycle in 26 women with inactive or quiescent systemic lupus erythematosus (SLE) and in 21 healthy women as controls. In all women studied, the menstrual cycle was proved to be ovulatory by ultrasound imaging and detection of an appropriately elevated value of peak serum progesterone. Blood samples were obtained for hormonal assay on several days of the menstrual cycle studied. Patients with SLE had lower peak and day-7 postovulation serum progesterone concentrations which were both significantly lower than those found in controls, whereas no major differences were observed for any of the other hormones analysed. Although the significance of the inadequate production of progesterone we have observed in SLE women with inactive disease is not clear, our data seem to indicate that a relative deficiency of progesterone might be considered among the potential predisposing factors for development of SLE in women.
Abstract: This study attempts to evaluate the adequacy of the erythropoietin (EPO) response in 42 anaemic patients with advanced human immunodeficiency virus (HIV) infection [30 with acquired immunodeficiency syndrome (AIDS) and 12 with AIDS-related conditions] by comparing their serum EPO levels with those found in a non-HIV reference population consisting of 36 patients with anaemia of chronic disorders (ACD) and 57 with iron deficiency anaemia (IDA). Although the average Hb concentration was similar in the three groups, the EPO level for HIV patients (mean +/- SEM, 64.3 +/- 7.7 mU/ml) did not differ significantly from that in ACD patients (45.3 +/- 8.3 mU/ml, P > 0.1), and both groups had a lower mean EPO level (P < 0.05 and P < 0.01 respectively) than IDA subjects (133.5 +/- 18.7 mU/ml). Thirteen HIV patients on zidovudine therapy showed similar mean Hb and EPO levels to those in the untreated patients. A significant inverse correlation between the log of serum EPO and the Hb values was observed in the three groups. However, this relationship was found to be stronger in IDA patients than in either HIV or ACD subjects (P < 0.001), with no difference between the two latter groups (P > 0.2). These data suggest that the EPO response is blunted in the anaemia associated with advanced HIV infection.
Abstract: Comparison was made of the aetiology and methods of diagnosis in two series of patients meeting the classic criteria of pyrexia of unknown origin during 1968-1981 and during 1982-1989 seen in the Department of Internal Medicine at La Paz University Hospital, Madrid, Spain. There was a statistically significant decrease in the percentage of infections and an increase in neoplasms and connective tissue disorders in the second series. The percentage of patients diagnosed by laparatomy was similar in both series but the diagnosis yield at laparotomy was greater in the second period. Pyrexia of unknown origin continues to be a condition which can defy clinical expertise in in spite of advances in diagnostic techniques.
Abstract: Serum erythropoietin (S-EPO) levels were measured in 50 patients with anaemia of chronic disorders (ACD), classified into three groups according to their aetiology: inflammatory (n = 20), infectious (n = 15) and neoplastic (n = 15). The inflammatory group showed a higher mean S-EPO level (mean value +/- SEM, 69 +/- 11 mU ml-1) than the neoplastic (43 +/- 5 mU ml-1; P less than 0.05) and infectious groups (27 +/- 4 mU ml-1; P less than 0.01). The S-EPO level in the inflammatory group also differed from that of 32 healthy controls (36 +/- 3 mU ml-1; P less than 0.05). Fourteen patients with added iron deficiency (12 subjects from the inflammatory group) showed the highest S-EPO concentration (72 +/- 17 mU ml-1). Conversely, S-EPO levels were lower in febrile subjects (12 patients with infection and five with malignancy) than in non-febrile patients (28 +/- 4 mU ml-1 vs. 55 +/- 7 mU ml-1; P less than 0.01). In the infectious group, the logarithm of S-EPO correlated directly with the haemoglobin and haematocrit values. We conclude that differences in S-EPO concentration in ACD may be further related to the patient's iron stores and temperature. A decrease in EPO production may contribute to the pathogenesis of ACD secondary to infection.
Abstract: Esophageal candidiasis, an opportunistic infection that generally occurs in the latest phases of infection due to the human immunodeficiency virus (HIV), is currently a diagnostic criterion for acquired immunodeficiency syndrome (AIDS). We recently treated one patient for esophageal candidiasis associated not with AIDS but with acute HIV infection. At follow-up 19 months later, he was well and had no symptoms related to infection with HIV. We reviewed nine previously reported cases of esophageal candidiasis associated with acute HIV infection. None of the patients involved had other predisposing illnesses or risk factors for candidiasis. The case described herein, together with those reviewed, supports a revision of the Centers for Disease Control's clinical definition of primary HIV infection to include esophageal candidiasis in the clinical spectrum. Moreover, the value of esophageal candidiasis as a diagnostic criterion for AIDS should be reassessed.
Abstract: The distribution of endogenous cobalamin among serum cobalamin-binding proteins was studied in 30 patients with active rheumatoid arthritis (RA) and 27 in clinical remission. The mean total serum cobalamin concentration (holo-transcobalamin I and II) was similar in both groups of patients, whereas mean apotranscobalamin II was significantly increased in patients with active RA. The clinical significance of this finding is not yet established but it might be a useful parameter for the evaluation of disease activity in RA.
Abstract: A series of 63 cases of fatal acute pulmonary thromboembolism (PTE) with available necropsy study was evaluated The diagnosis was established ante mortem in 20 cases (predictive index 31%). The diagnosis was only suspected in 2 of the 16 patients in whom PTE was associated with pneumonia (predictive index 12.5%, p less than 0.01), in 3 of the 26 cases if PTE associated with neoplasia (predictive index 11.5% p less than 0.01) and in 8 of the 41 cases with terminal disease (predictive index 19.5%, p less than 0.01). On the contrary, thrombophlebitis and relapsing PTE had a significative facilitation effect on the diagnosis (predictive indexes 53.3% and 52.6%, respectively; p less than 0.01). It was concluded that the presence of neoplasia, pneumonia or terminal illness make the diagnosis of pulmonary thromboembolism difficult.
Abstract: Five patients, two homosexuals and three drug abusers, with HIV-related severe thrombocytopenia, four of whom had also bleeding episodes, experienced a full remission of thrombocytopenia after 1,200 mg/day zidovudine treatment. None of the patients had acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. Platelet counts began an upward trend at the end of the 3rd week and reached values higher than 140 x 10(9)/l towards the end of the 8th week of treatment. Patient's platelets remained stable after more than 4 months of active treatment. This is the first report of zidovudine-induced long-term remission of HIV-associated severe thrombocytopenia.
Abstract: The cases of pulmonary thromboembolism (PTE) diagnosed in the clinical autopsies performed in our hospital during a 15-year period were reviewed. The incidence was 2.7% (63 cases). The most common disease associated with thromboembolism was cancer (41%). In 30 cases, thromboembolism involved more than 60% of the pulmonary circulation (group I), between 40% and 60% in 18 cases (group II), and less than 40% in 15 cases (group III). 30% of the embolisms were recurrent. A statistically significant correlation between the extension of the involved pulmonary circulation and the condition associated with thromboembolism was found. Whereas in patients with neoplasia the extension of pulmonary circulation involved by PTE was quite variable, the patients with cardiovascular disease or thrombophlebitis had PTE with invariably severe compromise of pulmonary vasculature (groups I and II).
Abstract: Pancreatic beta-cell and gut regulatory peptide responses were investigated in 13 healthy elderly and 12 young subjects (control group) after a standard meal test. In addition to hyperinsulinemia and hypergastrinemia, we found lower basal and postprandial total integrated responses (TIR) for gastric inhibitory polypeptide and bombesin in the elderly group. The mean postprandial TIR for neurotensin (NT) was significantly higher in the aged subjects, but the somatostatin response was suppressed in this group.
Abstract: The distribution of serum cobalamin-binding proteins was studied in 30 patients with low-grade multiple myeloma and in 26 patients with high-grade myeloma. The mean total cobalamin concentration (holotranscobalamin I and II) was similar in both groups of patients. We found a marked rise in total unsaturated binding cobalamin capacity mainly due to an increase in apotranscobalamin II (apo-TC II) in patients with high-grade myeloma. There was also a positive correlation between serum beta-2-microglobulin (B2M) and apo-TC II in myeloma patients. Our results indicate that pretreatment measurement of serum apo-TC II could supplement B2M as a prognostic guide.
Abstract: The concentrations of sex hormones were studied in 45 women with rheumatoid arthritis (RA). The patients were classified into two groups. Group I (premenopausal) consisted of 26 women and group II (postmenopausal) included 19 women. The two groups were compared with 40 control women (20 premenopausal and 20 postmenopausal). Age and weight were comparable in the 2 groups (controls and patients). The average plasma concentrations of oestradiol, progesterone and androgens were comparable in group I (patients with RA) and the control group (premenopausal women). On the other hand, the plasma concentration of androgens was statistically significantly higher in patients in group II by comparison with the postmenopausal controls. It thus seems that a hyperandrogenic situation may occur in menopausal women with RA, and this might have a beneficial clinical effect on the disease.
Abstract: Serum concentration of ferritin (Ft) and its glycosylated fraction (Ft-Gl) and intraerythrocytic ferritin (Ft-e) concentration were measured in 26 patients with anemia and active rheumatoid arthritis. Patients were divided into 2 groups according to the presence of anemia of chronic diseases (n = 13) or associated ferropenia. Unlike the first group, patients with associated ferropenia had lower concentration of the above parameters than 31 control subjects. The logarithmic value of FT (log FT) directly correlated with globular sedimentation velocity. Ft-Gl and log Ft-e correlated with transferrin saturation (r = 0.603, p less than 0.01 and r = 0.444, p less than 0.05). Log Ft-e also correlated with Ft (r = 0.504, p less than 0.01). The probability of ferropenia when Ft was 60 micrograms/l or lower was 0.91, and when Ft-e was 1.5 ag/cel or lower was 0.66. It is concluded that the ferropenic status in active rheumatoid anemia decreases the iron dependent synthesis of ferritin (Ft-Gl) more than that mediated by the acute phase response. The intraerythrocytic content is low due to the scanty iron supply to the erythroblast. Ft is more efficacious than Ft-e in the diagnosis of ferropenia.
Abstract: We have evaluated 100 biopsies of temporal artery carried out in the Hospital La Paz from 1972 to 1986. On the basis of the histological result and the final diagnosis we divided the patients in five groups: I, temporal arteritis/polymyalgia rheumatica with positive biopsy, 11 cases; II, temporal arteritis without polymyalgia symptoms and with positive biopsy, 16 cases; III, temporal arteritis with negative biopsy, 7 cases; IV, polymyalgia with negative biopsy, 14 cases; and V, other diagnoses, 43 cases. The number of diagnoses of temporal arteritis/polymyalgia rheumatica has increased throughout the recent years, although the positive biopsies/overall biopsies ratio has remained constant. Certain symptoms such as claudication, headache, amaurosis and Raynaud's phenomenon have a high predictive value of a positive result, but their sensitivity is low. In the 25 patients with polymyalgia, biopsy was positive in 11, out of which 4 did not have features of temporal arteritis. Biopsy was positive in 4 out of the 9 patients in whom it was repeated in the contralateral side. The diagnostic yield was higher in those cases in whom it was indicated for classical temporal arteritis symptoms, but we emphasize that there was a 19% positive rate in patients who presented with fever of unknown origin, while it was only 5.5% in those in whom a constitutional syndrome was being evaluated. We conclude that the use of temporal biopsy should be more widespread, as its cost is low and it has no side effects; therefore, it can achieve a great benefit for the patient with a shorter and less expensive hospital stay.
Abstract: A 55-year-old white male, with silicosis diagnosed 10 years earlier, presented massive proteinuria with microscopic hematuria, moderate renal failure and distal polyneuropathy. Bilateral renal angiography showed multiple intraparenchymal saccular aneurysms. Renal biopsy disclosed a focal segmental necrotizing glomerulonephritis and arteriolitis. After combined corticosteroid and immunosuppressive treatment, renal function improved and remained stable 6 months later.
Abstract: A prospective study to determine the carbohydrate metabolism in 23 intravenous drug users (IVDU) was carried out. 13 of them had no infection complications (group A), while the other 10 had acute associated infectious (group B). Both groups showed basal glycemia, insulin and glycosylated hemoglobin levels, similar to the control determinations. There were no correlations between these parameters and the hepatic function test alterations or the immunological changes in the IVDU. Our results showed that there were no alterations in the carbohydrates metabolism of the IVDU with a normal nutritional state, in spite of the well-known hypoglycemic effects of opiates in the experimental animal mode.
Abstract: In the present study the variability and diagnostic meaning of clinical features and common laboratory investigations were evaluated in a series of 220 patients with pulmonary thromboembolism (PTE) diagnosed by clinical means. The patients were classified into the two following groups: group I consisted of 102 critical patients admitted to an intensive care unit; group II consisted of 118 less-severely ill patients admitted to an ordinary hospital ward. Although clinical and laboratory features were nonspecific, the association of thrombotic risk factors in 88% of the patients permitted us to suspect the diagnosis of PTE within the initial three days in 71%. Chest radiogram was normal in 48%, ECG was normal in 32%, and contrast phlebography did not demonstrate phlebothrombosis in 16.4% of cases. The presumptive diagnosis was earlier (4 +/- 2 days) in group I than in group II patients (8 +/- 5 days) (p less than 0.01), and there was a significantly higher frequency of thoracic symptoms, hypoxemia, hypocapnia and radiologic and electrocardiographic abnormalities in group I patients. Chest radiogram and ECG were normal in only a small minority of these patients (9 and 7%, respectively). Overall mortality rate was 9.4% (20 patients, 14 from group I and 6 from group II). In 10 patients, all from group I, death took place within the first 72 hours after the diagnosis.
Abstract: Thirty-four children, aged 1-14 years, with severe chronic liver disease were studied to determine the incidence of chronic hemolytic anemia and the mechanism underlying it. Sixteen children were grouped as vitamin E-deficient patients (Group I, serum vitamin E level below 5.0 micrograms/ml) and compared with 18 vitamin E-sufficient children (Group II) and 20 healthy controls. Group I patients had a significantly lower hemoglobin level (11.6 +/- 0.4 g/dl) when compared with Group II (12.9 +/- 0.4 g/dl, less than 0.05), their RBC's were less resistant to H2O2-induced hemolysis (53.1 +/- 8.0% in Group I, vs. 1.07 +/- 0.23% in Group II), and the average hemolysis correlated with serum vitamin E levels. H2O2-induced hemolysis reverted to normal in five patients after vitamin E therapy. With respect to controls, cirrhotic children in both groups showed a slight increase in total RBC membrane lipids, but no difference in either phospholipid content or in cholesterol/phospholipid molar ratio that could have changed RBC membrane properties and sensitivity to lysis. In our experience, vitamin E-deficient cirrhotics have a slight degree of chronic hemolytic anemia and their RBC's are much more sensitive to H2O2 lysis, although this abnormal lysis susceptibility does not seem apparently related to membrane peroxidation.
Abstract: A 47-year-old man, was referred for evaluation of asymptomatic splenomegaly in September 1981, and a diagnosis of hairy cell leukemia (HCL) at the initial clinical stage was made. The patient remained asymptomatic until May 1985, when splenectomy was performed because of anemia and splenomegaly. Bone marrow and liver biopsy specimens showed diffuse infiltration by abnormal tartase resistant acid phosphatase (TRAP) positive lymphocytes with typical aspect of hairy cells. Four months later, he developed fever of unknown origin and, at laparotomy, diffuse retroperitoneal lymph node enlargement and metastatic liver nodules were seen. Lymph node and liver biopsy specimens showed diffuse infiltration by abnormal large lymphocytes, which bore monoclonal surface immunoglobulin M and light chain kappa. Only six cases of non-Hodgkin's lymphoma associated with HCL have been published to date. This report describes an additional case of immunoblastic B-cell lymphoma, preceded 4 years earlier by the diagnosis of HCL.
Abstract: We reviewed 2110 bone marrow aspirations from the same number of patients to establish the incidence and associations of peripheral and bone marrow basophilia. Of these, 125 cases of marrow basophilia (5.9% incidence) and 63 cases of peripheral basophilia (3.0% incidence) were identified. There were 33 patients with simultaneous marrow and peripheral basophilia, which was only significantly associated with chronic myelogenous leukemia (24 cases). Isolated peripheral basophilia was rarely seen (30 patients, 1.4% incidence) and it did not reflect any significant pathologic association. Marrow basophilia was significantly present in chronic myeloproliferative disorders, idiopathic myelodysplasia, certain erythrocyte disorders, such as iron deficiency anemia, and aplastic anemia. The incidence of marrow basophilia in patients with lymphoma, acute leukemia, or solid carcinoma was not significantly different from what it would be as a chance occurrence. Our findings suggest that marrow basophilia is a specific, but not sensitive, marker of myeloproliferative and dysmyelopoietic syndromes.
Abstract: Haematological variables in patients with eosinophilia and in healthy control subjects were studied in order to determine whether there were abnormalities in the coagulation system in patients. We found significantly elevated levels of fibrinogen, fibrin degradation products, platelet number and beta-thromboglobulin in patients. The abnormalities were not related to the causes of eosinophilia nor to its severity. This lack of correlation could be due to the heterogeneity of human peripheral blood eosinophils.
Abstract: We report the first outbreak of induced malaria among heroin users in Spain, and the first one caused by Plasmodium vivax in Europe. Five drug addicts from Madrid, who had never travelled to endemic areas, were admitted to hospital with fever and splenomegaly. Four had P. vivax malaria with low parasitaemia, ranging from 1 to 3% red blood cells. The fifth case was considered a "seropositive contact" because he had fever and positive malaria indirect fluorescent antibody test but negative blood smear. The source of infection was a young drug addict, who had often travelled to Equatorial Guinea. Another heroin user with a diagnosis of malaria refused to be admitted to our hospital for further study. All had shared contaminated injection equipment. Treatment with chloroquine was effective and none had recrudescence of malaria during a mean follow-up of six months. Drug addicts with unexplained fever may have been infected by malaria transmitted by sharing injections.
Abstract: Thirty-two patients with myelomatosis (3 with a solitary plasmocytoma and 29 with multiple myeloma) and neurological complications, from a group of 110 unselected patients with myelomatous disease were recorded. Spinal cord compression was the most frequent complication seen in 12 cases. In 9 subjects, it was the presenting symptom, and in 11 cases was caused by extradural plasmocytoma of the thoracic spine. Early decompressive laminectomy was curative in 3 cases, but in the rest, delay in diagnosis resulted in only partial recovery even with radiotherapy. Of the 6 patients with nerve root involvement, radiotherapy led to full recovery in 2 of 3 cases, and laminectomy resulted in complete improvement in 2 other cases. Peripheral polyneuropathy was seen in 8 cases, 2 related to systemic amyloidosis and 6 unassociated with amyloidosis. Both forms of neuropathy shared a slow progression, independent of the course of the myeloma. Acute encephalopathy, found in 6 cases, was due to hypercalcemia and/or serum hyperviscosity, and led to a significant shortening of mean survival. One patient had third cranial nerve palsy due to the overlying lesion of the skull base, and another suffered acute bacterial meningitis.
Abstract: One hundred pregnant women, not anemic and not receiving iron or vitamin supplements, were chosen at random among the three trimesters of pregnancy to determine the incidence of unexpected iron, plasma folate and/or cobalamin deficiency, and the significance of fluctuating levels of their respective binding proteins. Pregnant females had a nonsignificant fall in serum iron and a fourfold decline in serum ferritin in the 3rd trimester compared with 1st trimester values. There was a steady decrease in plasma cobalamin and cobalophilin levels in every trimester but no difference in transcobalamin II values. Unsaturated cobalamin (UBBC) and unsaturated transcobalamin binding capacity (UTCBC) were lower in the 1st trimester fully recovering afterwards. Plasma folate levels were not lower, although there was a steady reduction in total and unsaturated folate binding capacity throughout pregnancy.
Abstract: A 35-year-old man with definite Behçet's disease developed acute mitral and aortic regurgitation. Valvular disease, we believed, was another manifestation of this disease. Cardiac involvement in Behçet's disease and the role of prednisone therapy are discussed.
Abstract: The hospital records of one hundred and thirty-three patients with fever of unknown origin (FUO) were studied. An etiologic diagnosis had been made in 105 patients: 41 patients had an infection, 24 had a neoplasm, 17 had a connective tissue disease, and 23 had various diseases grouped under "miscellaneous." FUO was self-limiting in 25 of the remaining patients. Invasive procedures (arteriography, biopsy, laparoscopy, paparotomy) were necessary to establish a diagnosis in 67 patients, non-invasive tests (sero-immunologic, bacteriologic, conventional radiologic tests, clinical course and treatment response) were sufficient in 27 patients. In 11 patients, the cause of FUO was determined in necropsy. Thirty patients died of FUO: 6 patients with a neoplasm, 4 with a connective tissue disease, and 7 with diseases termed miscellaneous.
Abstract: We performed non-invasive assessment of cardiac size and function by clinical criteria, standard electrocardiography, chest X-ray, systolic time intervals and echo-cardiography in 27 patients with Paget's disease of bone and in 20 control subjects. The patients were divided into two groups on the basis of the degree of skeletal involvement (less than 15% in Group I and greater than 15% in Group II). No differences in heart size parameters of left ventricular performance were noted between Group I and controls. Cardiomegaly, increased left ventricular diastolic dimension and increased left ventricular mass indicative of ventricular hypertrophy were found in Group II compared to control subjects. In addition, patients with more extensive skeletal involvement had signs of depressed myocardial contractility, increased left ventricular volumes in diastole and systole and enlarged stroke volume, with no differences in echographic cardiac output compared to Group I and controls. The findings show an above normal incidence of cardiac enlargement and disturbed left ventricular performance in patients with Paget's disease and osseous lesions in greater than 15% of skeleton. The clinical implications of the altered cardiac function in patients with Paget's disease are briefly discussed.
Abstract: The case here reported of 72 year-old female with osteomalacia in whom an adult's Fanconi's syndrome with distal tubular involvement and a monoclonal IgG-lambda paraprotein were discovered. There was urinary excretion of lambda light chains without evidence of myeloma or amyloidosis. Such apparently unrelated entities might be subject to an unitary pathophysiological approach: the nephrotoxicity of light chains could cause a Fanconi's syndrome, which in turn would give rise to osteomalacia through phosphate depletion. It is noteworthy that in this patient the urinary excretion of light chains was of the lambda type, in contrast to similar cases described in the literature which presented mostly kappa chains. The likelihood of this patient developing myeloma or amyloidosis at a later stage is discussed.
Abstract: A patient is reported with stage IV-B Hodgkin's lymphoma, lymphocyte depletion type, and associated hypouricemia (1,7 mg/dl). In the few cases described of this association hypouricemia was secondary to a high renal clearance of urate, but in no case was the involved tubular level precisely delimited. In the present case the pyrazinamide and the probenecid tests were performed, disclosing the existence of a possible defect in the postsecretory reabsorptive phase which was improved by therapy. The different pathogenetic mechanisms described to explain this transitory tubular defect are reviewed.
Abstract: The appearance of amyloidosis during the course of multiple myeloma is a well known fact and has an overall incidence of 6 to 15%. However, the total transformation of a plasmocytoma into a voluminous amyloid tumor is a very rare event. A female patient was diagnosed of lambda light chain disease after developing a conspicuous rib plasmocytoma over the same region where a pathological fracture had appeared three years before. She was treated with discontinuous courses of melphalan and methyl-prednisolone, and developed a reversible nephrotic syndrome and a pathological fracture of the right clavicle. At necropsy there was generalized amyloidosis and complete substitution of the rib plasmocytoma by amyloid substance, with another important accumulation of amyloid in the region of the clavicular fracture. The present concepts on amyloidogenesis in multiple myeloma are reviewed, and the peculiarities of the present case together with the possible role of initiating factors and the effects of therapy are discussed. The case herein reported appears to represent a human model of focal amyloidogenesis in myeloma.
Abstract: The clinical, biological, and immunological alterations of 20 patients with histologically confirmed classical panarteritis nodosa have been studied. Characteristic angiographic changes were present in 14 cases. There were 14 males and six females, with a mean age of 50 years. The main clinical manifestations were: fever (90%), peripheral nervous system involvement (80%), renal involvement (65%), arterial hypertension (60%), arthropathy (80%), and cutaneous lesions (45%). In most cases there was elevated VSG and alpha 2-globulin, anemia and leukocytosis. HBsAg positivity was found in five patients. The immunological study revealed a polyclonal immunoglobulin increase, changes in the complement components, and a quantitative and qualitative decrease of T lymphocytes. Steroids and immunosuppressive treatment were given to eight patients, and steroids along to 11 patients. The clinical evolution of 17 patients was followed; four patients died, all of them belonging to the group treated with steroid alone.
Abstract: The fractional excretion of uric acid, calcium, phosphorus, magnesium and other ions, and the urinary acidifying capacity were studied in then patients with juvenile diabetes of short evolution and in a control group matched for age, sex, and body surface. The diabetic patients showed a hyperexcretion of uric acid, sodium, potassium, chloride and ammonium which was unrelated to the increment of glomerular filtration rate or to glucosuria, and could not be ascribed to diet. The pathophysiologic interpretation of these findings is discussed, concluding that they might be the result of an increase in the filtered load and the behaviour of the tubules in front of the glomerular hyperfunction or metabolic disturbance inherent to the diabetic condition.
Abstract: Renal function and renal size have been studied in ten early insulin-dependent diabetic patients and in ten matched control subjects. Glomerular filtration rate, renal plasma flow and radiological kidney size were determined in each subject. Glomerular filtration rate and renal plasma flow were increased in diabetics (mean +/- SD: 169.6 +/- 16.1 and 690.1 +/- 52.6 ml/min/1.73 m2, respectively) compared with controls (120.6 +/- 9.7 and 605.9 +/- 67.2 ml/min/1.73 m2; p less than 0.001 and p less than 0.01). Calculated kidney weight corrected to 1.73 m2 of body surface area was elevated in diabetics (385.2 +/- 29.0 g) with respect to controls (277.5 +/- 17.5 g; p less than 0.001). No significant differences were found between diabetics and control subjects when glomerular filtration rate was expressed per gram calculated kidney weight, while renal plasma flow was significantly lower in diabetics than control subjects when so expressed (p less than 0.01). A positive correlation was found between glomerular filtration rate, renal plasma flow and kidney size in both controls and diabetics (p less than 0.01 in all cases). These findings support the conclusion that in the early state of diabetes glomerular hyperfunction is related to enlargement of the kidneys and augmented renal plasma flow.
Abstract: Renal elimination of uric acid, calcium, phosphorus, sodium, potassium, chloride and magnesium and urinary acidification capacity were determined in ten insulin-dependent diabetics and in ten matched control subjects. The diabetics showed excessive excretion of uric acid, sodium, potassium, chloride and ammonia. Sodium, chloride and ammonia excretion fractions was also increased with respect to controls. The enhanced excretion of these substances in diabetics failed to relate to glomerular filtration rate, glycosuria or insulin requirements. These findings might be explained on the basis of glomerular filtration rate elevation, tubular response to this increment, and the underlying metabolic disturbances of diabetes.
Abstract: Angiographic studies were carried out on 21 patients with systemic necrotizing vasculitis. Four basic arterial anomalies were found: (1) saccular microaneurysms appeared in 62% of the patients (2) arterial thrombosis was seen in 81% of patients; (3) arterial stenosis occurred in 81%; and (4) lumen irregularities occurred in 90%. Alterations in the renal vascular flow were also observed in accordance with changes in the cortical medullary differentiation, heterogeneous nephrogram, and prolonged washout. Two patients showed regression of microaneurysms after immunosuppressive therapy. We found angiography to be a low-risk technique of use for diagnosis and followup studies on vasculitis.
Abstract: Fifteen patients with chronic active hepatitis (CAH) were tested in order to ascertain the site of tubular dysfunction in renal tubular acidosis (RTA) associated with CAH. Renal plasma flow and GFR were reduced in the patients compared to controls (P < 0.005). Underbasal and acidification conditions, twelve patients showed normal acid-base balance and net acid excretion, while three patients had basal hyperchloremic metabolic acidosis while passing alkaline urine and showing bicarbonaturia. A sustained acidification test showed adequate urinary acidification in these three patients. Bicarbonate loading carried out in two of the three patients showed a proximal tubular acidifying defect (Type 2 RTA), Distal RTA (Type 1 RTA) complicating CAH is widely known, but these data suggest that CAH can also involve the proximal convoluted tubule in isolation.
Abstract: The renal plasma flow (RPF), glomerular filtrate (GF), renal concentration strength and urinary acidification capacity in eight patients with alcoholic cirrhosis and five control subjects was studied. The maximum urinary acidification capacity was tested by means or arginine monochloride. In two patients, renal tubular acidosis (RTA) was observed. One patient manifested a slight decrease in RPF, GF, hyposthenuria, hyperchloremic metabolic acidosis and bicarbonaturia. The test for maintained acidification and the overload of bicarbonate indicated a mixed RTA. The other patient manifested incomplete distal RTA, which was briefly corrected with the administration of furosemide. These tubular defects were not associated with the loss of proteins, phosphates, glucose, aminoacids or renal lithiasis. Neither were they related to the serum levels of copper, globulins, or predisposition to hepatic encephalopathy. The association between hepatic cirrhosis and distal tubular acidosis is known, but until the present work, the fact that this hepatopathy can simultaneously affect the proximal and distal tubules had not been described.
Abstract: Clinical symptoms, biochemical analyses, immunologic status and angiographic findings corresponding to seven HBsAg positive patients with panarteritis nodosa and to 16 HBsAg negative patients with panarteritis nodosa have been compared. HBsAg positive cases showed a statistical significant higher incidences of Raynaud's phenomenon (p less than 0.05) and cardiopathies (p les than 0.05), as well as high occurrence of blood hypertension, artropathy, liver involvement and peripheral neuropathy. Significant differences in relation to cell immunity were not found. Humoral immune disturbances were more common among HBsAg positive patients, being hypergammaglobulinemia (p less than 0.01), IgM increase and decrease of complement factors (C3, C4 and C3PA) the most frequent abnormalities recorded. Angiographic studies revealed a high incidence of microaneurisms for the HBsAg positive group.
Abstract: Pulmonary function was studied in 22 patients with systemic lupus erythematosus without pulmonary clinical symptoms. The most striking features were: a) a restrictive functional pattern with hyperinflation, characterized by a decreased vital capacity and increased residual volume; b) alteration of the elastic properties of the lung, with increased pulmonary elastance; c) impairment of the alveolar-capillary gas transfer capacity, with very significant changes of the CO diffusion and arterio-alveolar gradients for O2 and CO2. No marked differences were found in functional disturbance among patients in the active or inactive phase of the disease.
