Pleural fluid procalcitonin to distinguish infectious from noninfectious etiologies of pleural effusions.

In this study we investigate the diagnostic value of pleural fluid procalcitonin (PCT) in distinguishing infectious and noninfectious etiologies of pleural effusion. We reviewed the medical records of 75 hospitalized patients who underwent thoracentesis between 2011 and 2012. Data on pleural fluid lactate dehydrogenase (LDH), protein, albumin, cell count and differential, pH, Gram stain and culture, cytology, triglyceride, cholesterol, amylase, and PCT were collected. Data on serum LDH, protein, albumin, prothrombin time, normalized, and blood culture were also collected. Pleural effusions were classified into 2 groups, infectious and noninfectious. There were 18 infectious pleural effusions (IPE) and 57 noninfectious pleural effusions (NIPE). Median pleural fluid PCT was 1.088 ng/mL (0.312-2.940 ng/mL) in IPE and 0.123 ng/mL (0.05-0.263 ng/mL) in NIPE, with a P value < 0.0001. Pleural fluid PCT > 0.25 ng/mL had a sensitivity of 77.78% and specificity of 74.14% for diagnosing an IPE. A subgroup analysis of PCT in exudative infectious effusions versus exudative noninfectious malignant/paramalignant effusions showed higher levels in the former. PCT is a novel biomarker for diagnosing infectious pleural effusion, and it would be worthwhile to investigate the role of pleural PCT in assessing severity of illness, risk stratification, and antibiotic stewardship in hospitalized patients with pleural effusions. Journal of Hospital Medicine 2016;11:363-365. 2016 Society of Hospital Medicine.

Procalcitonin induced cytotoxicity and apoptosis in mesangial cells: implications for septic renal injury.

OBJECTIVE AND DESIGN: Immuno-neutralization of procalcitonin (ProCT) has been shown to ameliorate experimental sepsis as well as the renal complications of this disease. Accordingly, we investigated the direct effect of ProCT on mesangial cells (MCs). MATERIAL: Primary culture of murine MCs. TREATMENT: ProCT (0.5, 1.0, 2.5, 5.0 ng/ml) for 2, 4, 6 h. METHODS: MCs were exposed in vitro to ProCT. Expression levels of IL-6, iNOS and TNF-α were determined by real time RT-PCR, Inflammatory pathways, and a panel of cytokines and chemokines involved in the process were investigated by PCR array; apoptosis/viability were evaluated in a multiplex assay and actin cytoskeleton alterations were examined by immunofluorescence (IF). RESULTS: ProCT caused an early elevation in both IL-6 and iNOS mRNA (2-4 h), and a later rise (6 h) in TNF-α mRNA. ProCT upregulated genes of proinflammatory pathways 5- to 24-fold compared to control. IF images revealed disruption of the actin cytoskeleton and retraction of cell bodies with loss of typical stellate or spindle shape phenotype. ProCT decreased MCs viability by 36 % compared to control cells and induced significant apoptosis. CONCLUSIONS: ProCT has direct cytotoxic properties and may play a role in septic acute kidney injury that is independent of endotoxemia or hemodynamic alterations.

Bacterial complications of respiratory tract viral illness: a comprehensive evaluation.

BACKGROUND: Respiratory tract infection is one of the most common reasons for hospitalization among adults, and recent evidence suggests that many of these illnesses are associated with viruses. Although bacterial infection is known to complicate viral infections, the frequency and impact of mixed viral-bacterial infections has not been well studied. METHODS: Adults hospitalized with respiratory illness during 3 winters underwent comprehensive viral and bacterial testing. This assessment was augmented by measuring the serum level of procalcitonin (PCT) as a marker of bacterial infection. Mixed viral-bacterial infection was defined as a positive viral test result plus a positive bacterial assay result or a serum PCT level of ≥ 0.25 ng/mL on admission or day 2 of hospitalization. RESULTS: Of 842 hospitalizations (771 patients) evaluated, 348 (41%) had evidence of viral infection. A total of 212 hospitalizations (61%) involved patients with viral infection alone. Of the remaining 136 hospitalizations (39%) involving viral infection, results of bacterial tests were positive in 64 (18%), and PCT analysis identified bacterial infection in an additional 72 (21%). Subjects hospitalized with mixed viral-bacterial infections were older and more commonly received a diagnosis of pneumonia. Over 90% of hospitalizations in both groups involved subjects who received antibiotics. Notably, 4 of 10 deaths among subjects hospitalized with viral infection alone were secondary to complications of Clostridium difficile colitis. CONCLUSIONS: Bacterial coinfection is associated with approximately 40% of viral respiratory tract infections requiring hospitalization. Patients with positive results of viral tests should be carefully evaluated for concomitant bacterial infection. Early empirical antibiotic therapy for patients with an unstable condition is appropriate but is not without risk.

Can serum procalcitonin levels help interpret indeterminate chest radiographs in patients hospitalized with acute respiratory illness?

BACKGROUND: Clinical diagnosis of pneumonia is difficult and chest radiographs often indeterminate, leading to incorrect diagnoses and antibiotic overuse. OBJECTIVE: To determine if serum procalcitonin (ProCT) could assist in managing patients with respiratory illness and indeterminate radiographs. DESIGN: Subjects were prospectively enrolled during 2 consecutive winters. SETTING: A 520-bed hospital in Rochester, NY. PATIENTS: Five hundred twenty-eight adults admitted with acute respiratory illness were enrolled. MEASUREMENTS: Serum ProCT, admission diagnoses, and chest radiographic findings were used to derive receiver operating characteristics curves to assess predictive accuracy of ProCT for the presence of infiltrates. RESULTS: Subjects with pneumonia had higher ProCT (median 0.27 ng/ml) than those with exacerbations of chronic obstructive pulmonary disease (0.08 ng/ml), acute bronchitis (0.09 ng/ml), or asthma (0.06 ng/ml). ProCT had moderate accuracy for the presence of infiltrates (area under curve [AUC] 0.72), when indeterminate radiographs were independently classified as infiltrates by a pulmonologist evaluating patients. CONCLUSIONS: ProCT may be useful in diagnosing pneumonia when chest radiographs are indeterminate.

Utility of serum procalcitonin values in patients with acute exacerbations of chronic obstructive pulmonary disease: a cautionary note.

BACKGROUND: Serum procalcitonin levels have been used as a biomarker of invasive bacterial infection and recently have been advocated to guide antibiotic therapy in patients with chronic obstructive pulmonary disease (COPD). However, rigorous studies correlating procalcitonin levels with microbiologic data are lacking. Acute exacerbations of COPD (AECOPD) have been linked to viral and bacterial infection as well as noninfectious causes. Therefore, we evaluated procalcitonin as a predictor of viral versus bacterial infection in patients hospitalized with AECOPD with and without evidence of pneumonia. METHODS: Adults hospitalized during the winter with symptoms consistent with AECOPD underwent extensive testing for viral, bacterial, and atypical pathogens. Serum procalcitonin levels were measured on day 1 (admission), day 2, and at one month. Clinical and laboratory features of subjects with viral and bacterial diagnoses were compared. RESULTS: In total, 224 subjects with COPD were admitted for 240 respiratory illnesses. Of these, 56 had pneumonia and 184 had AECOPD alone. A microbiologic diagnosis was made in 76 (56%) of 134 illnesses with reliable bacteriology (26 viral infection, 29 bacterial infection, and 21 mixed viral bacterial infection). Mean procalcitonin levels were significantly higher in patients with pneumonia compared with AECOPD. However, discrimination between viral and bacterial infection using a 0.25 ng/mL threshold for bacterial infection in patients with AECOPD was poor. CONCLUSION: Procalcitonin is useful in COPD patients for alerting clinicians to invasive bacterial infections such as pneumonia but it does not distinguish bacterial from viral and noninfectious causes of AECOPD.

Exogenous procalcitonin evokes a pro-inflammatory cytokine response.

OBJECTIVE AND DESIGN: Procalcitonin (ProCT) is increased in serum of septic patients and those with systemic inflammation. Endogenous levels of ProCT might influence the response of polymorphonuclear leukocytes (PMNs), independently of endotoxin, in clinical disease. SUBJECTS: Healthy human volunteers. TREATMENT: Recombinant human ProCT (rhProCT). METHODS: Whole blood and PMNs were exposed in vitro to exogenous rhProCT. Interleukin (IL)-6, IL-8, IL-10, IL-13, tumor necrosis factor-alpha (TNFα), IL-1ß, and macrophage inflammatory protein (MIP)-1ß (pg/ml) were measured by multiplex suspension bead-array immunoassay, and migration and phagocytosis were measured in PMNs. RESULTS: In a whole-blood model, a dose-dependent increase in IL-6, TNFα, and IL-1ß of the cell-free supernatant was noted. Pre-incubation with ProCT, at doses consistent with clinical sepsis, resulted in a decrease in PMN migration without alteration in phagocytosis of Staphylococcus aureus or indirect measurements of bacterial killing. CONCLUSION: Clinically relevant levels of ProCT influence immunologic responses that may contribute to systemic inflammatory response and septic shock.

Gut barrier dysfunction in critically ill surgical patients with abdominal compartment syndrome.

OBJECTIVES: This study investigated the effects of intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) on gut barrier function in critically ill surgical patients. METHODS: A prospective observational cohort study on patients with severe acute pancreatitis or abdominal sepsis admitted to an intensive care or high-dependency unit. Intra-abdominal pressure (IAP) and plasma levels of immunoglobulin G (IgG) and IgM antiendotoxin core antibodies (EndoCAb) and procalcitonin (ProCT) were measured serially. RESULTS: Among 32 recruited patients, 24 (75%) and 8 patients (25%) developed IAH and ACS, respectively. The state of ACS was associated with significant reductions in plasma IgG EndoCAb (P = 0.015) and IgM EndoCAb (P = 0.016) and higher concentrations of plasma ProCT (P = 0.056) compared with absence of ACS. Resolution of IAH and ACS was associated with significant recovery of plasma IgG EndoCAb (P = 0.003 and P = 0.009, respectively) and IgM EndoCAb (P = 0.002 and P = 0.003, respectively) and reduction in plasma ProCT concentration (P = 0.049 and P = 0.019, respectively). Negative correlations were observed between IAP and plasma IgG EndoCAb (P = 0.003) and IgM EndoCAb (P = 0.002). CONCLUSIONS: Intra-abdominal hypertension and ACS are associated with significantly higher endotoxin exposure and ProCT concentrations, suggestive of gut barrier dysfunction. Resolution of IAH and ACS is associated with evidence for recovery of gut barrier function.

Immunoneutralization of procalcitonin or its component peptides: a promising treatment of sepsis.

Sepsis and the severe systemic response syndrome are very common illnesses that are responsible for a great amount of morbidity and death. These closely related conditions are characterized by a remarkable increase in the prohormone ProCT (procalcitonin). ProCT is both a marker of sepsis and a harmful mediator of the disease. In the present issue of Clinical Science, in a study in rats with endotoxin shock, Tavares and Miñano used an antibody to a segment of N-ProCT (aminoprocalcitonin) that is part of the ProCT molecule, and confirmed that immunoneutralization of ProCT saves the animals from this severe illness. Furthermore, they extensively studied the epiphenomena associated with this immunoneutralization.

Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target.

The worldwide yearly mortality from sepsis is substantial, greater than that of cancer of the lung and breast combined. Moreover, its incidence is increasing, and its response to therapy has not appreciably improved. In this condition, the secretion of procalcitonin (ProCT), the prohormone of calcitonin, is augmented greatly, attaining levels up to thousands of fold of normal. This hypersecretion emanates from multiple tissues throughout the body that are not traditionally viewed as being endocrine. The serum values of ProCT correlate with the severity of sepsis; they recede with its improvement and worsen with exacerbation. Accordingly, as highlighted in this review, serum ProCT has become useful as a biomarker to assist in the diagnosis of sepsis, as well as related infectious or inflammatory conditions. It is also a useful monitor of the clinical course and prognosis, and sensitive and specific assays have been developed for its measurement. Moreover, it has been demonstrated that the administration of ProCT to septic animals greatly increases mortality, and several toxic effects of ProCT have been elucidated by in vitro experimental studies. Antibodies have been developed that neutralize the harmful effects of ProCT, and their use markedly decreases the symptomatology and mortality of animals that harbour a highly virulent sepsis analogous to that occurring in humans. This therapy is facilitated by the long duration of serum ProCT elevation, which allows for a broad window of therapeutic opportunity. An experimental groundwork has been established that suggests a potential applicability of such therapy in septic humans.

Diagnostic accuracy of chromogranin A and calcitonin precursors measurements for the discrimination of ectopic ACTH secretion from Cushing's disease.

CONTEXT: Inferior petrosal sinus sampling (IPSS) best discriminates between the two causes of ACTH-dependent Cushing's syndrome, Cushing's disease (CD) and ectopic ACTH secretion (EAS). However, when sampling is not available, adjunctive diagnostic tests might be helpful. Neuroendocrine tumors may secrete chromogranin A (CgA), calcitonin (CT), procalcitonin (ProCT), a fragment of the amino terminus of procalcitonin (NProCT), and/or ACTH. OBJECTIVE: The aim of the study was to evaluate the ability of serum CgA, CT, ProCT, or NProCT values to distinguish CD from EAS. DESIGN AND SETTING: We conducted a prospective pilot study at a clinical research center. SUBJECTS AND METHODS: Serum ProCT, NProCT, and CgA were measured in six patients with occult EAS diagnosed by IPSS, 25 CD patients, and 11 patients with histologically proven EAS. RESULTS: Nine EAS patients (53%) had at least one value above the reference range, including CgA alone (n = 4), ProCT alone (n = 3), CgA and ProCT (n = 1), and NProCT and ProCT (n = 1). Of nine (36%) CD patients with one or two abnormal values, seven had increased ProCT only, one had increased NProCT only, and one had increased CgA and ProCT. CgA had a positive predictive value of 83% and a negative predictive value of 70% for the diagnosis of EAS; other markers showed less discrimination. On pituitary magnetic resonance imaging, no EAS patient had an abnormality, whereas 21 of 25 patients with CD had a mass. CONCLUSION: These preliminary results suggest that an abnormal CgA and normal pituitary magnetic resonance imaging favor the diagnosis of EAS, but normal tumor markers do not exclude the diagnosis.

Procalcitonin levels in febrile infants after recent immunization.

BACKGROUND: Procalcitonin has been identified as a useful blood marker of serious bacterial infection in febrile infants. Many infants present with a febrile reaction after receiving immunizations. The effects of immunization on procalcitonin have not been investigated. METHODS: We performed a prospective observational cohort study at a large, urban pediatric emergency department. Infants or=38 degrees C were enrolled. Subjects were divided into 3 groups: infants with serious bacterial infection; subjects without serious bacterial infection who received recent (<48 hours) immunizations; and subjects without serious bacterial infection who did not recently receive immunizations. Procalcitonin was measured by using a quantitative immunometric assay. RESULTS: Over 13 months, procalcitonin was measured for 271 infants. There were 44 (16%) patients with serious bacterial infection, 35 in the recent-immunization group, and 192 in the no-recent-immunization group. The median procalcitonin level for serious bacterial infection was 0.53 ng/mL, for recent immunization was 0.29 ng/mL, and for no recent immunizations was 0.17 ng/mL. Procalcitonin values were elevated for patients with serious bacterial infection compared with patients both with and without recent immunizations. Compared with patients who had no recent immunizations, procalcitonin levels were elevated in patients with recent immunization. Using a cut point of 0.12 ng/mL, the sensitivity of procalcitonin for serious bacterial infection was 96%, specificity was 23%, and negative predictive value was 96%. Two patients with recent immunization who had serious bacterial infection were identified with this cut point. CONCLUSIONS: Among febrile infants with recent immunization, procalcitonin levels are increased compared with patients with fever and no identified bacterial infection. Despite this increase, procalcitonin can still reliably discriminate infants with serious bacterial infection.

Procalcitonin in young febrile infants for the detection of serious bacterial infections.

OBJECTIVES: The objectives of the study were (1) to study the test performance of procalcitonin for identifying serious bacterial infections in febrile infants

Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations.

OBJECTIVE: The use of procalcitonin (ProCT) as a marker of several clinical conditions, in particular, systemic inflammation, infection, and sepsis, will be clarified, and its current limitations will be delineated. In particular, the need for a more sensitive assay will be emphasized. For these purposes, the medical literature comprising clinical studies pertaining to the measurement of serum ProCT in various clinical settings was examined. DATA SOURCE AND SELECTION: A PubMed search (1965 through November 2007) was conducted, including manual cross-referencing. Pertinent complete publications were obtained using the MeSH terms procalcitonin, C-reactive protein, sepsis, and biological markers. Textbook chapters were also read and extracted. DATA EXTRACTION AND SYNTHESIS: Available clinical and other patient data from these sources were reviewed, including any data relating to precipitating factors, clinical findings, associated illnesses, and patient outcome. Published data concerning sensitivity, specificity, and reproducibility of ProCT assays were reviewed. CONCLUSIONS: Based on available data, the measurement of serum ProCT has definite utility as a marker of severe systemic inflammation, infection, and sepsis. However, publications concerning its diagnostic and prognostic utility are contradictory. In addition, patient characteristics and clinical settings vary markedly, and the data have been difficult to interpret and often extrapolated inappropriately to clinical usage. Furthermore, attempts at meta-analyses are greatly compromised by the divergent circumstances of reported studies and by the sparsity and different timing of the ProCT assays. Although a high ProCT commonly occurs in infection, it is also elevated in some noninfectious conditions. Thus, the test is not a specific indicator of either infection or sepsis. Moreover, in any individual patient, the precipitating cause of an illness, the clinical milieu, and complicating conditions may render tenuous any reliable estimations of severity or prognosis. It also is apparent that even a febrile septic patient with documented bacteremia may not necessarily have a serum ProCT that is elevated above the limit of functional sensitivity of the assay. In this regard, the most commonly applied assay (i.e., LUMItest) is insufficiently sensitive to detect potentially important mild elevations or trends. Clinical studies with a more sensitive ProCT assay that is capable of rapid and practicable day-to-day monitoring are needed and shortly may be available. In addition, investigations showing that ProCT and its related peptides may have mediator relevance point to the need for evaluating therapeutic countermeasures and studying the pathophysiologic effect of hyperprocalcitonemia in serious infection and sepsis.

Procalcitonin has bioactivity at calcitonin receptor family complexes: potential mediator implications in sepsis.

CONTEXT: Sepsis is a major cause of death in the United States and accounts for approximately 50% of the fatalities in intensive care units. Serum procalcitonin (ProCT) levels are markedly elevated in sepsis and correlate positively with severity of the illness and mortality, however, little is known about the biological activity of ProCT. OBJECTIVE: To explore the biological activity of purified human ProCT at the calcitonin (CT) family of receptors. DESIGN: Human ProCT was purified from the TT medullary thyroid carcinoma cell line. Human CTa receptor or human CT receptor-like receptor (CLR) was transiently expressed in COS-7 cells alone or together with individual receptor activity-modifying proteins (RAMPs) to generate the CTa (CT) receptor, the AMY1 (amylin) receptor, the CGRP1 (CT gene-related peptide) receptor, and the AM1 and AM2 (adrenomedullin) receptors. Biological activity of ProCT was assessed by measurement of cAMP accumulation. RESULTS: ProCT was effectively inert at CTa, AM1, and AM2 receptors. In contrast, it was a potent partial agonist (50-60% of the CGRP efficacy) of the CGRP1 receptor with an EC50 as high as 0.56 nM, although the potency was batch dependent. ProCT also displayed weak partial agonist activity at the AMY1 receptor with an EC50 of approximately 100 nM. Moreover, ProCT also robustly inhibited CGRP-dependent cyclic adenosine monophosphate responses at the CGRP1 receptor. CONCLUSIONS: Our data provide a potential molecular mechanism for the observation that ProCT appears to be toxic while CGRP treatment appears to be beneficial in animal models of sepsis.

Correlation of procalcitonin and cytokine expression with dehiscence of wartime extremity wounds.

BACKGROUND: Despite technological advances in the treatment of severe extremity trauma, the timing of wound closure remains the subjective clinical decision of the treating surgeon. Traditional serum markers are poor predictors of wound-healing. The objective of this study was to evaluate the cytokine and chemokine profiles of severe extremity wounds prior to closure to determine if wound effluent markers can be used to predict healing. METHODS: Serum and effluent (exudate) samples were collected prospectively from adult volunteers with multiple high-energy penetrating extremity wounds sustained during military combat. Samples were collected prior to definitive wound closure or flap coverage. Wounds were followed clinically for six weeks. The primary clinical outcome measures were wound-healing and dehiscence. Control serum samples were collected from normal age and sex-matched adult volunteers. All samples were analyzed for the following cytokines and chemokines: procalcitonin; eotaxin; granulocyte macrophage colony stimulating factor; interferon (IFN)-gamma; interleukin (IL)-1 through 8, 10, 12, 13, and 15; IFN-gamma inducible protein-10; monocyte chemotactic protein-1; macrophage inflammatory protein-1alpha; the protein regulated on activation, normal T expressed and secreted (RANTES); and tumor necrosis factor (TNF)-alpha. RESULTS: Fifty wounds were analyzed in twenty patients. Four of the fifty wounds dehisced. An increased rate of wound dehiscence was observed in patients with a concomitant closed head injury as well as in those with an associated arterial injury of the affected limb (p < 0.05). Among the serum chemokines and cytokines, only serum procalcitonin levels correlated with wound dehiscence (p < 0.05). Effluent analysis showed that, compared with wounds that healed, wounds that dehisced were associated with elevated procalcitonin, decreased RANTES protein, and decreased IL-13 concentrations (p < 0.05). No wound with an effluent procalcitonin concentration of <220 pg/mL, an IL-13 concentration of >12 pg/mL, or a RANTES protein concentration of >1000 pg/mL failed to heal. CONCLUSIONS: Effluent procalcitonin, IL-13, and RANTES protein levels as well as serum procalcitonin levels correlate with wound dehiscence following closure of severe open extremity wounds. These preliminary results indicate that effluent biomarker analysis may be an objective means of determining the timing of traumatic wound closure.

Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children.

OBJECTIVE: Children with cancer often develop febrile illnesses after cytotoxic chemotherapy. Determining which children have serious bacterial infections in this vulnerable period would be valuable. We evaluated the ability of a rapid and sensitive assay for the concentration of calcitonin precursors (CTpr) as a sensitive diagnostic marker for bacterial sepsis in febrile, neutropenic children and determined the utility of measuring cytokines to improve the predictive value of this approach. DESIGN: Prospective cohort study. SETTING: Academic children's hospital. PATIENTS: Fifty-six children (aged 5 months to 17 yrs) with a known malignancy who presented with fever and neutropenia. INTERVENTIONS: Serial blood samples were obtained (admission, 24 hrs, and 48 hrs), and concentrations of CTpr, interleukin-6, and interleukin-8 were determined. Demographic and laboratory data from the patients were collected from the medical record. MEASUREMENTS AND MAIN RESULTS: Sixteen (29%) of the children met the criteria for bacterial sepsis. Plasma levels of CTpr and interleukin-8, but not interleukin-6, were increased at all time points in children with sepsis compared with those without sepsis. CTpr at 24 and 48 hrs after admission were reliable markers for sepsis (area under the curve = 0.92 and 0.908, respectively). Logistic regression using CTpr at 24 hrs in addition to interleukin-8 at 48 hrs produced the best-fit models associated with sepsis. Using cutoff values of CTpr >500 pg/mL and interleukin-8 >20 pg/mL produced a screening test for sepsis with 94% sensitivity and 90% specificity. CONCLUSIONS: Our data show the utility of a rapid and sensitive assay for CTpr combined with interleukin-8 as a highly sensitive and specific diagnostic marker of bacterial sepsis in febrile, neutropenic children. The use of these markers as a clinical tool may allow for better prognostication for clinicians and may eventually lead to more targeted therapies for this heterogeneous population.

Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency.

We have previously described the only reported case of human proprotein convertase 1 (PC1) deficiency, in a female (Subject A) with obesity, hypogonadism, hypoadrenalism, and reactive hypoglycemia. We now report the second case of human PC1 deficiency (Subject B), also due to compound heterozygosity for novel missense and nonsense mutations. While both subjects shared the phenotypes of obesity, hypoadrenalism, reactive hypoglycemia, and elevated circulating levels of certain prohormones, the clinical presentation of Subject B was dominated by severe refractory neonatal diarrhea, malabsorptive in type. Subsequent investigation of Subject A revealed marked small-intestinal absorptive dysfunction, which was not previously clinically suspected. We postulate that PC1, presumably in the enteroendocrine cells, is essential for the normal absorptive function of the human small intestine. The differences in the nature and severity of presentation between the two cases cannot readily be explained on the basis of allelic heterogeneity, as the nonsense and missense mutations from both subjects had comparably severe effects on the catalytic activity of PC1. Despite Subject A's negligible PC1 activity, some mature ACTH and glucagon-like peptide 17-36(amide) were detectable in her plasma, suggesting that the production of these hormones, at least in humans, does not have an absolute dependence on PC1. The presence of severe obesity and the absence of growth retardation in both subjects contrast markedly with the phenotype of mice lacking PC1 and suggest that the precise physiological repertoire of this enzyme may vary between mammalian species.

In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue.

Circulating levels of calcitonin precursors (CTpr), including procalcitonin (ProCT), increase up to several thousand-fold in human sepsis, and immunoneutralization improves survival in two animal models of this disease. Herein, we analyzed inflammation-mediated calcitonin I gene (CALC I) expression in human adipocyte primary cultures and in adipose tissue samples from infected and noninfected patients with different levels of serum ProCT. In ex vivo differentiated adipocytes, the expression of CT mRNA increased 24-fold (P < 0.05) after the administration of Escherichia coli endotoxin (lipopolysaccharide) and 37-fold (P < 0.05) after IL-1beta administration by 6 h. ProCT protein secretion into culture supernatant increased 13.5-fold (P < 0.01) with lipopolysaccharide treatment and 15.2-fold (P < 0.01) with IL-1beta after 48 h. In coculture experiments, adipocyte CT mRNA expression was evoked by E. coli-activated macrophages in which CT mRNA was undetectable. The marked IL-1beta-mediated ProCT release was inhibited by 89% during coadministration with interferon-gamma (IFNgamma). In patients with infection and markedly increased serum ProCT, CT mRNA was detected in adipose tissue biopsies. Hence, we demonstrate that ProCT, which is suspected to mediate deleterious effects in sepsis and inflammation, is a novel product of adipose tissue secretion. The inhibiting effect of IFNgamma on IL-1beta-induced CT mRNA expression and on ProCT secretion might explain previous observations that serum ProCT concentrations increase less in systemic viral compared with bacterial infections.