Enhanced fitness and renal function in Type 2 diabetes.

AIMS: To investigate the renal effects of fitness in people with diabetes with mild renal dysfunction. METHODS: The effect of a 12-week exercise programme on estimated GFR in 128 people with diabetes was evaluated. RESULTS: All cardiometabolic variables improved after 12 weeks of supervised exercise. Although there was a modest 3.9% increase in estimated GFR from baseline in the 128 people who completed the study, those with baseline chronic kidney disease stages 2 and 3 were found to have significant (6 and 12%, respectively; p < 0.01) improvements in post-exercise estimated GFR. Moreover, 42% of the people with chronic kidney disease stage 3 improved to chronic kidney disease stage 2 after the intervention. CONCLUSION: Short-term exercise improves renal function in those with more moderate baseline chronic kidney disease. Thus, renal function appears to be responsive to enhanced physical fitness. Being a strong and modifiable risk factor, enhanced fitness should be considered a non-pharmacological adjunct in the management of diabetic kidney disease.

Salivary and serum biomarkers of inflammation in a man with metastatic medullary thyroid carcinoma and hyperreactive gingiva: a fourteen year odyssey.

A peripheral (gingival) fibroma, a gingival cyst and hyperplastic gingivitis occurred simultaneously in a man with metastatic medullary thyroid carcinoma (MCT). The gingival growths and hyperplasia appeared to be related to poor oral hygiene rather than to the MTC. Despite the patient's improved oral hygiene, the hyperplastic gingivitis and peripheral fibroma recurred, and a new peripheral fibroma and gingival cyst developed, which prompted reconsideration of a link with the MTC. MTC cells secrete calcitonin (CT), procalcitonin (ProCT) and growth factors; the patient's serum CT and ProCT were several fold higher than normal. The patient's salivary CT and ProCT also were elevated, but α-amylase and epidermal growth factor (EGF) were not, compared to three healthy controls. A possible link between the MTC and gingival hyper-reactivity due to CT and/or ProCT promoting inflammatory cytokines, and the utility of salivary ProCT as an indicator of periodontitis in this patient were explored further. Unstimulated whole saliva and serum were collected from the patient followed by a standard periodontal examination before periodontal treatment, and 3 weeks and 3 months after treatment. This cycle was repeated 7 months after the previous periodontal treatment. The saliva was assayed for ProCT and the serum was assayed for ProCT, high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6) and proadrenomedullin (ProADM). The results were analyzed for correlations among the severity of periodontitis and the biomarkers/cytokines. Only the salivary ProCT was correlated with the severity of periodontitis, i.e. it was higher just before and lower at 3 weeks and 3 months after each periodontal treatment. The patient's salivary ProCT content also was much higher than reported elsewhere. The other biomarkers/cytokines were within normal ranges. Our findings indicate that salivary ProCT is independent of serum ProCT and therefore may be a useful marker for moderate to severe periodontitis in patients with MTC. The greatly elevated salivary and serum CT and ProCT, and a trend toward correlation between the serum CRP and ProCT suggest a pro-inflammatory link between the MTC and the hyperreactive gingiva in this patient. Further studies are warranted to determine whether hyperplastic gingivitis and gingival growths, such as cysts and fibromas, occur with unusual frequency in patients with MTC.

Salivary procalcitonin and periodontitis in diabetes.

Periodontitis and type 2 diabetes are co-morbid conditions, both characterized by infectious susceptibility. We investigated procalcitonin (ProCT) levels in the serum and saliva of persons with periodontitis and type 2 diabetes (n = 20), to determine if these levels are altered by periodontitis activity or by hyperglycemia. Persons with severe periodontitis showed higher levels of salivary-ProCT than did those with moderate periodontitis (241 +/- 71 vs. 77 +/- 516 pg/mL, p = 0.02) and higher levels than did healthy control individuals (118 +/- 26 pg/mL, p = 0.05). Salivary-ProCT levels were correlated with bleeding-on-probing (r = 0.45, p = 0.05), as well as with HgbA(1c) (r = 0.49, p = 0.03). Salivary levels of ProCT were higher than serum levels for the periodontitis/diabetes group (152 +/- 37 vs. 78 +/- 17 pg/mL, p = 0.02) and the control group (118 +/- 146 vs. 48 +/- 17 pg/mL, p = 0.01). Persons with periodontitis and type 2 diabetes have salivary-ProCT levels that reflect their degree of periodontitis activity and hyperglycemia. This study demonstrates, for the first time, the presence of procalcitonin (ProCT), an established serum marker of infection, in saliva.

Salivary and serum procalcitonin and C-reactive protein as biomarkers of periodontitis in United States veterans with osteoarthritis or rheumatoid arthritis.

Serum procalcitonin (ProCT) is elevated in response to bacterial infections, whereas high sensitivity C-reactive protein (hsCRP) is a nonspecific inflammatory marker that is increased by excess adipose tissue. We examined the efficacy of ProCT and hsCRP as biomarkers of periodontitis in the saliva and serum of patients with arthritis, which is characterized by variable levels of systemic inflammation that potentially can confound the interpretation of inflammatory biomarkers. Blood and unstimulated whole saliva were collected from 33 patients with rheumatoid arthritis (RA) and 50 with osteoarthritis (OA). Periodontal status was assessed by full mouth examination and patients were categorized as having no/mild, moderate or severe periodontitis by standard parameters. Salivary and serum ProCT and hsCRP concentrations were compared. BMI, diabetes, anti-inflammatory medications and smoking status were ascertained from the patient records. Differences between OA and RA in proportionate numbers of patients were compared for race, gender, diabetes, adiposity and smoking status. Serum ProCT was significantly higher in arthritis patients with moderate to severe and severe periodontitis compared with no/mild periodontitis patients. There were no significant differences in salivary ProCT or salivary or serum hsCRP in RA patients related to periodontitis category. Most of the OA and RA patients were middle aged or older, 28.9% were diabetic, 78.3% were overweight or obese, and slightly more than half were either current or past smokers. The OA and RA groups differed by race, but not gender; blacks and males were predominant in both groups. The OA and RA groups did not differ in terms of controlled or uncontrolled diabetes, smoking status or BMI. The RA patients had been prescribed more anti-inflammatory medication than the OA patients. Our results demonstrate that circulating ProCT is a more discriminative biomarker for periodontitis than serum hsCRP in patients with underlying arthritis. Any elevation in salivary and serum hsCRP due to periodontitis apparently was overshadowed by differences among these patients in factors that influence CRP, such as the extent of inflammation between RA and OA, the extent of adipose tissue, the use of anti- inflammatory medications and smoking status. Although our study showed no differences in salivary ProCT related to severity of periodontitis, this biomarker also may be useful with further refinement.

Reduced acetylation of procainamide by para-aminobenzoic acid.

Acetylation is the major route of metabolism of many drugs including the antiarrhythmic agent procainamide. Coadministration of para-aminobenzoic acid was observed to decrease the biotransformation of procainamide to N-acetylprocainamide in a patient with rapid acetylation kinetics. In view of the distinct antiarrhythmic and toxic properties of procainamide and N-acetylprocainamide, the observed drug interference may have great clinical relevance in long-term oral antiarrhythmic therapy and in instances where other drugs converge for acetylation.

Ubiquitous expression of the calcitonin-i gene in multiple tissues in response to sepsis.

Calcitonin precursors (CTpr), including procalcitonin, are important markers and also potentially harmful mediators in response to microbial infections. The source and function of CTpr production in sepsis, however, remains an enigma. In the classical view, the transcription of the CT-I gene is restricted to neuroendocrine cells, in particular the C cells of the thyroid. To better understand the pathophysiology of CTpr induction in sepsis, we used an animal model analog to human sepsis, in which bacterial infection is induced in hamsters by implanting Escherichia coli pellets ip. Compared with control hamsters, levels of CTpr were elevated several fold in septic plasma and in nearly all septic hamster tissues analyzed. Unexpectedly, CT-messenger RNA was ubiquitously and uniformly expressed in multiple tissues throughout the body in response to sepsis. Notably, the transcriptional expression of CT-messenger RNA seemed more widely up-regulated in sepsis than were classical cytokines (e.g. tumor necrosis factor-alpha and interleukin-6). Our findings, which describe a potentially new mechanism of host response to a microbial infection mediated by CTpr, introduce a new pathophysiological role for the CT-I gene.

Serum calcitonin precursors in sepsis and systemic inflammation.

High serum levels of the calcitonin (CT) prohormone, procalcitonin (pro-CT), and its component peptides occur in systemic inflammation and sepsis. Using two different assays, we undertook a prospective study to determine the utility of serum precalcitonin peptides (pre-CT) as markers in this condition. Twenty-nine patients meeting criteria for the systemic inflammatory response syndrome were studied daily in two intensive care units. Sera were collected, and APACHE II scores were determined until recovery or death. All patients had markedly elevated serum pre-CT. Prognostically, peak values were the most important. The highest values portended mortality, and a lower level could be ascertained below which all patients survived. Peak pre-CT levels were significantly higher in patients with infection documented by blood cultures than in those patients with no documented infection from any source (P < 0.05). Mature CT remained normal or only moderately elevated. Compared with the serum pre-CT levels, receiver operating characteristic curve analysis revealed that the APACHE II scores, although more cumbersome, were better overall predictors of mortality. Thus, pre-CT is an important serum marker for systemic inflammatory response syndrome and is predictive of outcome. It also provides data concerning the presence of severe infection and may prove to be clinically useful for proactive patient care.

Immunoneutralization of procalcitonin as therapy of sepsis.

Prior studies have demonstrated that the prohormone, procalcitonin (ProCT), and its component calcitonin precursors (CTpr) are increased in the serum of septic patients, correlate with the severity of the illness, and persist for relatively long periods of time. Animal studies in septic hamsters have revealed that the administration of ProCT is toxic and that immunoneutralization with IgG that is reactive to this molecule significantly improves survival. A large animal model of a very rapidly lethal polymicrobial sepsis has been developed in the pig in order to measure continuous physiological and metabolic parameters and also to compare the effects in this animal of an immunoneutralization, which is performed late in the course of the disease, to an identical, but early, therapy. Based upon the physiological and metabolic parameters, the late therapy, which was initiated during the fourth hour at a time when pigs were nearly moribund, was found to be as beneficial as early therapy. In both late and early therapy, the only animals to survive at the predetermined time of euthanasia were those which had received immunoneutralization therapy.

Humoral markers of severity and prognosis of critical illness.

Despite the considerable advances made in understanding the pathophysiology of systemic inflammation during critical illness, clinical progress has been elusive as it remains a very deadly condition. Cortisol and thyroid hormone levels can be as predictive of outcome as the commonly used severity parameters (i.e. APACHE). Indeed, levels of endocrine humoral substances such as arachidonic acids, nitric oxide, endothelin, calcitonin precursors, leptin and adenosine correlate with the severity and outcome of critical illness. Furthermore, calcitonin precursors represent a potentially new hormokine paradigm, being transcriptionally activated in all cells in response to infection. The cytokines are immune markers that often correlate with severity and outcome, but their release is transient. In contrast, the so-called acute phase proteins, such as C-reactive protein and serum amyloid A, are highly sensitive to inflammatory activity and can be important markers of severity and outcome. Leukocyte esterase, adhesion molecules, platelet activating factor and activated protein C are additional humoral immune markers; the replacement of the latter has been shown to be a promising therapeutic option. Natriuretic peptides are neurocrine humoral markers that have important cardiovascular implications. The level of macrophage migrating inhibitory factor, released by the pituitary, is elevated in sepsis and counteracts glucocorticoid action. Cellular markers to severe stress include the enhanced expression of protective substances in the form of heat shock proteins. High mobility group-1 is a DNA-binding protein and a late mediator of the inflammatory response. Apoptotic markers such as the soluble fas ligand are also elevated in inflammation. In summary, during critical illness, the endocrine, immune and nervous systems elaborate a multitude of humoral markers, the roles of which merit further scrutiny in order to improve therapeutic outcome.

Thermal regulatory dysfunction of growth hormone in classical heat stroke.

Growth hormone (GH) secretion associated with classical (non-exertional) heat stroke (HS) was evaluated in 26 HS victims and 10 control (non heat-exhausted) subjects during the annual Hajj in Makkah, Saudi Arabia. On admission to the HS treatment unit, the GH level was 1.54 +/- 0.14 ng/ml (approximately 3.5-fold higher in the HS victims compared to controls; p = 0.005). The GH levels subsequently declined by 78% by 24 h. The categorized GH response was significantly associated with survival for those subjects with a GH level of < 5.53 ng/ml by 6 h (chi-squared test; p = 0.06). In those patients who died (N = 6), there was a continued increase in GH levels from the time of admission, which peaked at 6 h. In those patients who survived, the GH levels peaked at the time of admission and declined rapidly thereafter. There was a direct correlation of age and GH level upon admission (p = 0.02), as well as to peak GH (p = 0.041). However, there was no relationship of GH level to either body core temperature or the cooling time. In summary, HS induced significant GH secretion. The degree of GH response was not related to the body core temperature and was more pronounced in older individuals and in those that died. Although patients with GH deficiency and HS are characterized by anhidrosis/hypohidrosis, there does not appear to be dysfunction of GH response to heat stress-associated HS. In contrast, a vigorous GH response at 6 h suggested a worse outcome.

Procalcitonin and proinflammatory cytokine interactions in sepsis.

Immunoneutralization of procalcitonin (ProCT), a putative mediator of sepsis, has been shown to increase survival in an animal model of sepsis. To better understand the role that ProCT plays in the sepsis cascade, we studied the relationship of this hormone to the proximal proinflammatory mediators, IL-1beta and TNFalpha. Hamsters were made septic by i.p. implantation of Escherichia coli-impregnated agar pellets. A time line study of serum IL-beta, TNFalpha, and ProCT levels showed that the increase in the cytokines was transient and less than 2-fold over baseline, whereas ProCT increased >100-fold by 12 h and remains elevated through 24 h. TNFalpha (400 microg/kg) was injected into healthy animals, inducing an elevation in ProCT that was 25-fold greater than controls. ProCT (30 microg/kg) was given to healthy and septic animals. In healthy animals, there was no significant elevation in serum IL-1beta or TNFalpha levels. In septic animals, IL-1beta was modestly blunted at 3 h but not at 12 h, and there was no change in TNFalpha levels. ProCT did not initiate or enhance IL-1beta or TNFalpha expression; however, the massive and sustained elevation of this hormone seen in sepsis can be induced by the proximal cytokine, TNFalpha. This study suggests that ProCT is a secondary mediator that might augment and amplify but does not initiate the septic response. Immunoneutralization of ProCT may prove to be an important clinical strategy, in view of its sustained elevation and the difficulty in initiating therapy for sepsis during the early phases of illness.

Procalcitonin and proinflammatory cytokine in interactions in sepsis.

Immunoneutralization of procalcitonin (ProCT), a putative mediator of sepsis, has been shown to increase survival in an animal model of sepsis. To better understand the role that ProCT plays in the sepsis cascade, we studied the relationship of this hormone to the proximal proinflammatory mediators, IL-1beta and TNFalpha. Hamsters were made septic by i.p. implantation of Escherichia coli-impregnated agar pellets. A time line study of serum IL-beta, TNFalpha, and ProCT levels showed that the increase in the cytokines was transient and less than 2-fold over baseline, whereas ProCT increased >100-fold by 12 h and remains elevated through 24 h. TNFalpha (400 microg/kg) was injected into healthy animals, inducing an elevation in ProCT that was 25-fold greater than controls. ProCT (30 microg/kg) was given to healthy and septic animals. In healthy animals, there was no significant elevation in serum IL-1beta or TNFalpha levels. In septic animals, IL-1beta was modestly blunted at 3 h but not at 12 h, and there was no change in TNFalpha levels. ProCT did not initiate or enhance IL-1beta or TNFalpha expression; however, the massive and sustained elevation of this hormone seen in sepsis can be induced by the proximal cytokine, TNFalpha. This study suggests that ProCT is a secondary mediator that might augment and amplify but does not initiate the septic response. Immunoneutralization of ProCT may prove to be an important clinical strategy, in view of its sustained elevation and the difficulty in initiating therapy for sepsis during the early phases of illness.

Comparative studies of hamster calcitonin from pulmonary endocrine cells in vitro.

The lung-associated peptide calcitonin (CT) has been localized by immunocytochemical means to discrete pulmonary endocrine (PE) cells. A long-term cell culture of CT-staining PE cells has been established. The molecular configuration of immunoreactive (iCT) from PE cell extracts was determined by gel chromatography, revealing predominantly large molecular weight forms of iCT. The size distribution characteristics of PE Cell iCT were similar to those of intact hamster lung. In contrast, hamster thyroid extracts contain predominantly 4000 dalton iCT (presumed monomer) and apparent iCT fragments. The culture media of the PE cells were found to contain mainly 4000 dalton iCT. We conclude that although the predominant forms of iCT found within cultured PE cells are distinct from those found within thyroidal C-cells, both iCT producing cells release mainly the monomer into the media. Malignant human bronchial carcinoid cells store predominantly monomeric iCT while secreting large molecular weight forms of iCT. Since the PE cell is the putative precursor cell to neuroendocrine malignancies, the disparity noted in the processing of CT may have significant pathobiological implications.

Glutamate as a CNS transmitter. I. Evaluation of glucose and glutamine as precursors for the synthesis of preferentially released glutamate.

Slices of the molecular layer of the dentate gyrus of the hippocampal formation were incubated with either [14C]glucose, [14C]pyruvate or 14C glutamine and the efflux of endogenous and radioactive glutamate was monitored under various conditions. After prelabeling with either [14C]glutamine or [14C]glucose elevation of K+ concentration to 56 mM (Ca2+ free) increased efflux of endogenous and [14C]glutamate. Introduction of Ca2+ into the elevated K+ medium further increased the efflux of endogenous glutamate and radioactive glutamate derived from any of the precursors tested. In glutamine containing media, the increase in glutamate efflux as well as basal efflux was considerably higher than in the absence of glutamine and the specific activity of glutamate release was higher than that in tissue. Thus glutamine was superior to glucose or pyruvate as precursor and most specifically labeled the putative transmitter pool of glutamate. Similar experiments were carried out 4 and 14 days after a unilateral lesion in the entorhinal cortex which provides about 60% of the total synaptic input to the dentate granule cells. The Ca2+ dependent release of glutamate derived from either glucose or glutamine was markedly reduced on the operated side. This result suggests that the transmitter pool of glutamate is in perforant path terminals and can be synthesized from glucose or glutamine.

Modulation of pulmonary bombesin by nicotine and vagotomy.

In pregnant hamsters, three transplacental injections of the ganglionic agonist nicotine resulted in a dose-dependent decrease in the concentration of mammalian bombesin (MB) in the lungs of neonatal (1 day old) animals. This decrease in neonatal MB did not occur if nicotine was given only once during gestation, or when it was given three times in conjunction with the ganglionic antagonist mecamylamine. In one week old animals born of mothers who had been exposed to three doses of nicotine during gestation, lung MB had returned to control levels. When nicotine was injected into neonatal animals, lung MB acutely increased. Right sided vagotomy to young hamsters resulted in an increase in the ratio of lung MB (right vs. left lobe) 1 week after surgery. Administration of nicotine to vagotomized animals resulted in decreased total lung MB and normalization of the MB ratio. Thus, nicotine has a potent modulatory influence on lung MB during fetal and neonatal development and maturation. This influence is also present in young animals that are subjected to partial denervation. Our hypothesis is that the innervation of pulmonary neuroendocrine (PNE) cells influences both PNE cell growth and its synthetic function. PNE MB, which is an epithelial and neoplastic growth factor, may play a role in this response.

Evidence for cigarette smoke-induced calcitonin secretion from lungs of man and hamster.

In hamsters, acute cigarette smoke inhalation increased serum levels of the hormone calcitonin; and, in humans, smoking of two high-nicotine content cigarettes increased serum and urine levels of this hormone. The source of this immunoreactive calcitonin (iCT) does not appear to be the thyroid gland, since previously thyroidectomized patients demonstrated a similar response. In the hamster, the increased serum iCT levels were accompanied by a decreased lung tissue iCT content and hypocalcemia. It is suggested that the source of the cigarette smoke-induced hypercalcitonemia is the lung, possibly from the iCT-containing pulmonary neuroendocrine (PNE) cells. Moreover, this response appears to be dependent on the nicotine content of the cigarettes.

Late pulmonary sequela following burns: persistence of hyperprocalcitonemia using a 1-57 amino acid N-terminal flanking peptide assay.

Seven patients were evaluated at a mean duration of 8.4 yr after sustaining inhalational injury associated with burns. At the time of re-examination, the patients were asymptomatic and had normal chest X-rays, and arterial blood gases. Three of the seven patients had abnormally elevated serum calcitonin levels. The spirometry (FEV1) measurements showed an inverse trend to that of the serum calcitonin levels. The elevated calcitonin levels had an abnormal predominance of the procalcitonin component as assessed by several region specific antisera. The serum calcitonin also showed a significant correlation with the hormone level which had been obtained at the time of prior discharge from the hospital (r = 0.91). Although there appears to be no or minimal chronic pulmonary sequela to inhalational injury in burns by pulmonary testing, we speculate that the hyperprocalcitonemia in some of the patients may reflect a long-term hyperplastic response of the bronchio-epithelial pulmonary neuroendocrine cells. The potential significance of this and other lung-associated endocrine markers is discussed.

Procalcitonin and its component peptides in systemic inflammation: immunochemical characterization.

BACKGROUND: The systemic inflammatory response syndrome (SIRS) is a marked, generalized response to a variety of injuries, if infection is implicated, the term "sepsis" is used. Systemic inflammatory response syndrome/sepsis, which is initiated by proinflammatory cytokines, has been found to be associated with increased serum levels of the prohormone of calcitonin, procalcitonin (ProCT) and its aminoterminus peptide (nProCT). The serum levels of ProCT and nProCT are very useful markers for SIRS/sepsis, and may be used to follow the course, the response to therapy, and/or the prognosis. We studied the serum levels and distribution of ProCT and its component peptides in normal persons for comparison with similar immunochemical and separatory studies in patients with neuroendocrine cancer and with SIRS/sepsis of various etiologies. METHODS: We studied pooled and extracted serum of 13 normal subjects, and sera of patients with neuroendocrine cancer and SIRS/sepsis, using region-specific immunoassays, gel filtration, and high performance liquid chromatography. RESULTS: Normal sera contained small but measurable levels of the intact ProCT molecule, nProCT, a conjoined calcitonin-calcitonin carboxyterminal peptide (CT:CCP-I), CCP-I, free mature CT, and calcitonin gene-related peptide (CGRP). Sera from neuroendocrine cancer usually contained high levels of these peptides. In such cases, free mature CT was always increased, the mean ratio of the intact ProCT to free CT being 168 +/- 68. Gel filtration and HPLC studies of patients with SIRS/sepsis revealed markedly increased levels of ProCT, nProCT, and CT:CCP-I in varying proportions. Mature CT was normal to minimally elevated. The ratio of ProCT to free CT was 2,900 +/- 800. Although serum CGRP is commonly increased in neuroendocrine cancer, it was very low or undetectable in SIRS/sepsis. CONCLUSIONS: These studies indicate that ProCT and its component peptides circulate in normal persons. The serum of patients with SIRS/sepsis contains greatly increased levels of ProCT, nProCT and often, CT:CCP-I. However, in this condition, post-translational processing is incomplete, resulting in mature CT levels that are normal or minimally elevated. In contrast, patients with neuroendocrine cancer have considerably high mature CT levels. Interestingly, although serum CGRP levels often are high in neuroendocrine cancer, they are low in SIRS/sepsis. The marked hyperprocalcitonemia of SIRS/sepsis is probably a consequence of the pro-inflammatory cytokine cascade, and appears to be secreted in a constitutive fashion; the cell(s) of origin of this remarkable hypersecretion is unknown. There is a very marked positive correlation between serum levels of ProCT and nProCT, and the lower level of sensitivity for nProCT may make its measurement a more useful marker for early or mild SIRS/sepsis.

Calcitonin gene-related peptide expression in sepsis: postulation of microbial infection-specific response elements within the calcitonin I gene promoter.

BACKGROUND: Recently, we reported an unexpected ubiquitous expression of calcitonin (CT)-mRNA in a hamster peritonitis model of sepsis. Using this animal model,we undertook a study to further investigate the pattern of expression of the calcitonin I (CALC-I) gene and CT gene-related peptide (CGRP)-mRNA in sepsis. METHODS: Live Escherichia coli impregnated in agar pellets were implanted in the peritoneal cavities of hamsters. Twelve hours after sepsis induction, the septic and healthy control animals were sacrificed and tissues and peritoneal macrophages were collected. CGRP-mRNA content was evaluated by reverse transcription polymerase chain reaction (RT-PCR), quantitated by the Taq-Man technique, and compared with the mRNA expression of CT, tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6). The 5' untranslated regions of the mRNA and potential alternative splicing sites were identified by 5' rapid amplification of cDNA ends. RESULTS: We found a tissue-wide, ubiquitous and uniform expression of CGRP-mRNA in all septic tissues examined. CGRP-mRNA was detectable by RT-PCR in various extraneuronal and extrathyroidal septic tissues, but not in healthy control tissues. As found for CT-mRNA in our earlier studies, CGRP-mRNA seemed to be more specifically up-regulated as compared with other classical cytokines (ie, II-6 and TNF-alpha). Importantly, the 5' untranslated sequence in control and septic thyroid was similar to the sequence obtained from septic spleen. CONCLUSIONS: We postulate the presence of microbial infection-specific response elements in the CALC-I gene promotor, which, upon a specific stimulus, override the tissue-selective expression pattern. This new form of endocrine plasticity may be of importance in the response to systemic inflammation.

Growth hormone deficiency in adults: a review.

For more than 35 years, growth hormone (GH) has been used to promote linear growth in GH-deficient children. Previously, GH replacement in adults was limited to the supply of human pituitary-derived GH. In addition, until recently, GH replacement was not deemed clinically indicated. With the introduction of recombinant human prion-free GH, replacement therapy in GH-deficient adults has become feasible, and its use has burgeoned. In this review, recent studies on GH therapy in healthy and GH-deficient adults are evaluated to provide a rational basis for the widened scope of its clinical application.