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 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.

Factors associated with failure to achieve a glycated haemoglobin target of <8.0% in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The aim of this study was to identify the clinical features of participants in the standard therapy arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) glycaemia trial who failed to reach the glycated haemoglobin (HbA1c) target. We analysed 4685 participants in the standard therapy arm, comparing participants who reached the HbA1c target of <8.0% with those whose HbA1c level was ≥8.0% 12 months after randomization. Baseline and 12-month clinical characteristics were compared. At 12 months after randomization, 3194 participants had HbA1c <8.0% and 1491 had HbA1c ≥8.0%. Black race [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.61-0.89; p = 0.002], severe hypoglycaemia (OR 0.57, CI 0.37-0.89; p = 0.014) and insulin use (OR 0.51, CI 0.40-0.65; p < 0.001) were associated with failure to reach HbA1c goal at 12 months in the adjusted model. Even with free medications, free visits with clinicians and aggressive titration of medications, >30% of participants in the standard arm of the ACCORD trial had an HbA1c ≥8.0% at 1 year. Participants who were black, had severe hypoglycaemia and were on insulin were more likely to have an above-target HbA1c concentration after 12 months on the standard protocol.

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 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.

Calcitonin precursor levels in human medullary thyroid carcinoma.

DESIGN: The hormonal serum marker for the presence and course of patients with medullary thyroid cancer (MTC) is the mature calcitonin (CT) peptide. Other CALC-1 gene products such as the 116-amino acid polypeptide prohormone, procalcitonin, as well as its component calcitonin precursors (CTpr) may also be increased in their sera. We performed a study to evaluate the clinical utility of serum levels CTpr in these patients. METHODS: Twenty-one patients with MTC (9 males, 12 females; 23-76 years of age) were evaluated. The diagnosis was confirmed by histologic examination, except for 2 (a proven RET mutation plus an abnormal pentagastrin-stimulated CT level). Nine patients had postoperative hypercalcitoninemia and 3 of these died. The specific assay for mature CT was a commercial immunoradiometric assay (hCT-IRMA); the immunoluminometric assay for CTpr (B.R.A.H.M.S Diagnostica, Berlin, Germany) detects intact procalcitonin and the free CT:CT carboxypeptide-1. RESULTS: All patients had detectable serum CTpr. These levels considerably exceeded those of mature CT, averaging 7.6-fold greater. CTpr levels correlated positively with mature CT (r = 0.61; p < 0.001). After pentagastrin administration, there was a parallelism of response between the two assays. Whenever there were known metastases, CTpr increased markedly. CONCLUSION: This study demonstrates the universal presence of CTpr in the blood of patients with MTC. The measurement of these peptides may offer a new dimension to the clinical evaluation of this malignancy.

Calcitonin precursors: early markers of gut barrier dysfunction in patients with acute pancreatitis.

BACKGROUND: Severe acute pancreatitis is associated with an early increase in intestinal permeability and endotoxemia. Endotoxin is a potent stimulator for the production and release of procalcitonin and its components (calcitonin precursors; [CTpr]). The aim of this study is to evaluate the role of plasma CTpr as an early marker for gut barrier dysfunction in patients with acute pancreatitis. METHODS: Intestinal permeability to macromolecules (polyethylene glycol 3350), serum endotoxin and antiendotoxin core antibodies, plasma CTpr, and serum C-reactive protein (CRP) were measured on admission in 60 patients with acute pancreatitis. Attacks were classified as mild (n = 48) or severe (n = 12) according to the Atlanta criteria. RESULTS: Compared with mild attacks of acute pancreatitis, severe attacks were significantly associated with an increase in intestinal permeability index (median: 0.02 vs. 0.006, P < 0.001), the frequency of endotoxemia (73% vs. 41%, P = 0.04), and the extent of depletion of serum IgM antiendotoxin antibodies (median: 43 MMU vs. 100 MMU, P = 0.004). Plasma CTpr levels were significantly elevated in patients with severe attacks compared with mild attacks on both the day of admission and on day 3 (median: 64 vs. 22 fmol/mL, P = 0.03; and 90 vs. 29 fmol/mL, P = 0.003 respectively). A positive and significant correlation was observed between the admission serum endotoxin and plasma CTpr levels on admission (r = 0.7, P < 0.0001) and on day 3 (r = 0.96, P < 0.0001), and between plasma CTpr on day 7 and the intestinal permeability index (r = 0.85, P = 0.0001). In contrast, only a weak positive correlation was observed between peak serum levels of CRP and plasma CTpr on admission (r = 0.3, P = 0.017) and on day 7 (r = 0.471, P = 0.049), as well as between CRP and each of the admission serum endotoxin (r = 0.3, P = 0.03) and the intestinal permeability index (r = 0.375, P = 0.007). CONCLUSIONS: In patients with acute pancreatitis, plasma concentrations of CTpr appear to reflect more closely the derangement in gut barrier function rather than the extent of systemic inflammation.

Calcitonin precursors in the prediction of severity of acute pancreatitis on the day of admission.

BACKGROUND: Calcitonin precursors are sensitive markers of inflammation and infection. The aim of this study was to evaluate the role of plasma calcitonin precursor levels on the day of admission in the prediction of severity of acute pancreatitis, and to compare this with the Acute Physiology And Chronic Health Evaluation (APACHE) II scoring system. METHODS: Plasma concentrations of calcitonin precursors were determined on admission in 69 patients with acute pancreatitis. APACHE II scores were calculated on admission. Attacks were classified as mild (n = 55) or severe (n = 14) according to the Atlanta criteria. Plasma calcitonin precursor levels were determined with a sensitive radioimmunoassay. RESULTS: On the day of hospital admission, plasma levels of calcitonin precursors were significantly greater in patients with a severe attack compared with levels in those with a mild attack of pancreatitis (median 64 versus 25 fmol/ml; P = 0.014), but the APACHE II scores were no different (median 9 versus 8; P = 0.2). The sensitivity, specificity, positive predictive and negative predictive values, and accuracy for the prediction of severe acute pancreatitis were 67, 89, 57, 93 and 85 per cent respectively for plasma calcitonin precursor levels higher than 48 fmol/ml, and 69, 45, 23, 86 and 50 per cent respectively for an APACHE II score greater than 7. Differences in the specificity and accuracy of the two prognostic indicators were significant (P < 0.001 and P = 0.001 respectively). A plasma calcitonin precursor concentration of more than 160 fmol/ml on admission was highly accurate (94 per cent) in predicting the development of septic complications and death. CONCLUSION: The assay of plasma calcitonin precursors on the day of admission to hospital has the potential to provide a more accurate prediction of the severity of acute pancreatitis than the APACHE II scoring system.

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.

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.

A case of myoedema and normal pressure hydrocephalus.

A cachectic 55-year-old man presented with ataxia and metabolic instability. On physical examination, he had prominent myoedema in all muscle groups. In addition, a CT scan and lumbar puncture showed extensive nonobstructive hydrocephalus. Further clinical evaluation revealed elevated creatine phosphokinase and liver enzyme levels, although the patient was euthyroid. The patient improved neurologically and metabolically with supportive therapy but the myoedema persisted. Previous cases have emphasized that myoedema is a localized, electrically silent, benign myopathic disorder of unknown cause. As with a previous case with ventricular enlargement, myoedema may be part of systemic pathology. Finally, as in most other reports, myoedema is a rare condition; only 3 cases (of 44) with palpable (but not visible) myoedema were uncovered in this study.

Effects of anti-inflammatory agents on serum levels of calcitonin precursors during human experimental endotoxemia.

Calcitonin precursor (CTpr) levels are both markers and mediators of inflammation. The duration of their elevation after intravenous endotoxin challenge and the effects of anti-inflammatory therapies were studied in 52 subjects. CTpr levels maximized at 24 h in all subjects. At 7 days (n=4), after levels of acute-phase cytokines and C-reactive protein had normalized, CTpr levels remained 2-4-fold above baseline levels. The elimination half-life of CTpr levels ranged from 26.9 to 45.7 h. At 24 h, endotoxin and ibuprofen (compared with endotoxin alone) increased CTpr levels approximately 2-fold (P=.03), whereas soluble tumor necrosis factor receptor blunted the increase in CTpr levels by 2-3-fold (P=.0015). However, soluble interleukin-1 receptor failed to alter the increase in CTpr levels. Thus, the fact that anti-inflammatory agents may alter CTpr levels resulting from a single stimulus must be considered when CTpr is used as a clinical marker. Of importance, this study reveals that anti-inflammatory agents may modulate the CTpr level, which is a potential toxic mediator of inflammation.

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.

Late immunoneutralization of procalcitonin arrests the progression of lethal porcine sepsis.

BACKGROUND: Procalcitonin (ProCT) is becoming increasingly recognized as a mediator as well as a marker of sepsis. Serum ProCT concentrations rise soon after induction of sepsis and remain elevated over a prolonged period of time. In contrast, many pro-inflammatory cytokines, e.g., tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), rise and decline early in the course of sepsis. Researchers have improved survival in animal models of sepsis by prophylactically blocking IL-1beta and TNF-alpha with immunotherapy, but therapeutic treatment has been less successful in clinical trials. We hypothesized that the sustained elevation of ProCT in the serum would allow for effective therapeutic immunoneutralization of this peptide late in the course of sepsis. METHODS: Lethal polymicrobial sepsis was induced in 10 castrated, male Yorkshire pigs by intraabdominal spillage of cecal contents (1 gm/kg) and intraabdominal instillation of 2 x 10(11) cfu of a toxigenic strain of E. coli (O18:K1:H7). The treated group (n = 5) received an intravenous infusion of purified rabbit antiserum to the aminoterminus of porcine ProCT. The control group (n = 5) received nonreactive, purified rabbit IgG. The purified antiserum was infused to all animals 3 h after the induction of sepsis, at which time very severe physiologic dysfunction was manifest, and many of the animals appeared to be preterminal. Physiologic and metabolic parameters were measured until death or for 15 h after induction of sepsis, at which time all surviving animals were euthanized. RESULTS: Therapeutic immunoneutralization of serum ProCT improved most measured physiologic and metabolic parameters in septic pigs. Specifically, there was a significant increase in mean arterial pressure, urine output and cardiac index in all animals treated with ProCT antibody. Serum creatinine was significantly lower in treated animals. Although acidosis was not as severe in treated animals, as indicated by higher pH values and lower lactate concentrations, these results did not achieve statistical significance. Significantly, 11 h after the induction of sepsis there was 100% mortality in the control group while only one animal in the treated group expired. CONCLUSION: The prolonged elevation of ProCT concentrations in sepsis allows neutralization of this peptide to be effective during the course of this disorder. These findings suggest that immunoneutralization of ProCT may be a useful treatment in clinical situations where sepsis is already fully established.

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.

Disordered calcium homeostasis of sepsis: association with calcitonin precursors.

BACKGROUND: Hypocalcemia and increased serum levels of calcitonin precursors are common in critically ill patients, especially in those with sepsis. We investigated calcium homeostasis in such patients. PATIENTS AND METHODS: Serum concentrations of total and ionized calcium and known factors influencing or reflecting calcium homeostasis were measured in 101 consecutive patients of a medical intensive care unit. Calcitonin precursor levels were determined using a highly sensitive radioimmunoassay. RESULTS: Critical illness per se was associated with decreased serum total and ionized calcium levels, which correlated with the severity of the underlying disease as measured by the APACHE II score. In addition, total and ionized hypocalcemia was more pronounced with increasing severity of infection (P < 0.02), and occurred in parallel with a marked increase of calcitonin precursors (P < 0.001). Mature calcitonin levels, however, remained normal. Changes of serum ionized calcium concentrations from admission to discharge correlated significantly with changes in the serum calcitonin precursor concentration (r2 = - 0.14, P < 0.001). Circulating vitamin D levels, parathyroid hormone levels and other markers reflecting calcium homeostasis did not correlate with the severity of infection. CONCLUSIONS: In critically ill patients with sepsis, markedly elevated circulating calcitonin precursors might play a role in the development of the pronounced hypocalcemia. The specific calcitonin precursor(s) responsible for this effect and the pathophysiological mechanism remain to be elucidated.

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.

Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy.

Limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM) are autosomal recessive disorders caused by mutations in the dysferlin gene on chromosome 2p13. The authors studied a large Russian family with both LGMD2B and MM. All affected individuals, as well as one preclinical boy with dystrophic changes on muscle biopsy, were found to be homozygous for a novel dysferlin mutation, TG573/574AT (Val67Asp). This finding supports the view that additional factors (e.g., modifier genes) contribute to the phenotypic expression of causative mutations in dysferlinopathies.