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OBJECTIVE: To report 8 patients with Sjögren's syndrome (SS) and localized nodular cutaneous amyloidosis and to examine serologic and immunohistologic findings that may link the 2 diseases. METHODS: The databases for 3 amyloidosis centers were searched for patients with localized nodular cutaneous amyloidosis and SS. Eight patients with this combination were identified, and clinical, serologic, and histologic parameters were retrospectively evaluated. RESULTS: Among the 8 patients with a clinical diagnosis of SS, 6 fulfilled the American-European Consensus Group criteria for SS. All of the patients were women in whom SS had been diagnosed at a median age of 47 years (range 30-61 years) and amyloid had been diagnosed at a median age of 60 years (range 42-79 years). The presence of the immunoglobulin light chain type of amyloid (AL amyloid) was confirmed in 4 patients. In 3 of these 4 patients as well as 2 other patients, a light chain-restricted plasma cell population was observed near the amyloid deposits. Progression to systemic amyloidosis was not observed in any patient during a median followup of 3.5 years. CONCLUSION: SS should be considered in patients with cutaneous amyloidosis. The combination of cutaneous amyloidosis and SS appears to be a distinct disease entity reflecting a particular and benign part of the polymorphic spectrum of lymphoproliferative diseases related to SS. [ABSTRACT FROM AUTHOR]

Background: We investigated the role of the clinical pulmonary infection score (CPIS), serum levels of procalcitonin (PCT), C-reactive protein (CRP), and serum amyloid A (SAA) in the detection of patients with early ventilator-associated pneumonia (VAP).Methods: Observational study in a university hospital. In 58 patients with severe brain injury receiving mechanical ventilation, CPIS, PCT, CRP and SAA were evaluated at ICU entry and at days 3 to 4 of hospital stay for VAP diagnosis (confirmed by endotracheal aspirate or BAL cultures).Results: We found the following: (1) PCT at entry was increased in patients who later had early VAP develop (25 patients) compared to no VAP (median, 1.4 ng/mL; 25-75 percentiles, 0.14-0.78; vs median, 0.2 ng/mL; 25-75 percentiles, 0.76-2.4, p<0.001; sensitivity, 76%; and specificity, 75%); (2) CPIS increased at the day of VAP diagnosis, compared to entry (median, 6.6+/-1.1 vs 1.5+/-1.1, p<0.001; sensitivity, 97%; specificity, 100%), while other serum inflammatory markers did not change; and (3) deterioration in oxygenation and changes in tracheal secretions were the main determinants of CPIS changes.Conclusions: PCT may be a useful marker to predict which patients subsequently have early VAP. The CPIS could help as an early way to detect the patients with early VAP and who need further diagnostic testing. [ABSTRACT FROM AUTHOR]

Merlini G, Westermark P (Amyloid Center, Biotechnology Research Laboratory, University Hospital IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy; and Rudbeck Laboratory, Uppsala University, Uppsala, Sweden). The systemic amyloidoses: clearer understanding of the molecular mechanisms offers hope for more effective therapies (Review). J Intern Med 2004; 255: 159–178. Knowledge about the systemic amyloidoses has increased considerably during the last few years. This group of diseases is characterized by great biochemical variability, including at least 11 different amyloid fibril proteins and a remarkable range of clinical manifestations. With the understanding that the pathogenesis is different in the various forms of amyloidosis, it is now being increasingly accepted that an early and accurate diagnosis, including that of the underlying biochemical nature, is crucial for a successful treatment. The elucidation of the molecular mechanisms involved in amyloidogenesis is at the basis of the recent blossoming of new, innovative and more effective therapeutic approaches. [ABSTRACT FROM AUTHOR]

Amyloid A (SAA) and procalcitonin (PCT) have been reported as useful indicators of inflammation. Our aim was to assess the utility of SAA and PCT in establishing the severity of acute pancreatitis in comparison to C-reactive protein (CRP): Thirty-one patients with acute pancreatitis enrolled within 24 hr from the onset of pain and 31 healthy subjects were studied. Nineteen patients had mild acute pancreatitis, and 12 had severe pancreatitis. Serum SAA, PCT, and CRP were measured in all subjects at admission and, in acute pancreatitis patients, during the following five days. Patients with acute pancreatitis had serum concentrations of SAA, PCT, and CRP significantly higher (P < 0.001) than those of healthy subjects during the entire study period. Using cutoff values ranging from 240 to 250 mg/liter for SAA, from 0.252 to 0.255 ng/ml for PCT, and from 12.8 to 12.9 mg/dl for CRP, the sensitivity (calculated on patients with severe pancreatitis), the specificity (calculated on patients with mild pancreatitis), and the efficiency (calculated as the percentage of correct classifications) were 76.8%, 69.3%, and 72.4% for SAA; 21.7%, 83.2%, and 58.2% for PCT; and 60.9%, 89.1%, and 77.6% for CRP. In conclusion, the sensitivity of SAA is significantly higher than that of PCT and CRP in assessing the severity of pancreatitis, whereas PCT and CRP had a specificity significantly higher than SAA. The accuracy and efficiency were similar for SAA and CRP, and both these markers had an accuracy and efficiency significantly higher than those of PCT. [ABSTRACT FROM AUTHOR]

The solution structure and stability of N-terminally truncated ²2-microglobulin (”N6²2-m), the major modification in ex vivo fibrils, have been investigated by a variety of biophysical techniques. The results show that ”N6²2-m has a free energy of stabilization that is reduced by 2.5 kcal/mol compared to the intact protein. Hydrogen exchange of a mixture of the truncated and full-length proteins at ¼M concentrations at pH 6.5 monitored by electrospray mass spectrometry reveals that ”N6²2-m is significantly less protected than its wild-type counterpart. Analysis of ”N6²2-m by NMR shows that this loss of protection occurs in ² strands I, III, and part of II. At mM concentration gel filtration analysis shows that ”N6²2-m forms a series of oligomers, including trimers and tetramers, and NMR analysis indicates that strand V is involved in intermolecular interactions that stabilize this association. The truncated species of ²2-microglobulin was found to have a higher tendency to self-associate than the intact molecule, and unlike wild-type protein, is able to form amyloid fibrils at physiological pH. Limited proteolysis experiments and analysis by mass spectrometry support the conformational modifications identified by NMR and suggest that ”N6²2-m could be a key intermediate of a proteolytic pathway of ²2-microglobulin. Overall, the data suggest that removal of the six residues from the N-terminus of ²2-microglobulin has a major effect on the stability of the overall fold. Part of the tertiary structure is preserved substantially by the disulfide bridge between Cys25 and Cys80, but the pairing between ²-strands far removed from this constrain is greatly perturbed. [ABSTRACT FROM PUBLISHER]

We have recently described an anti-β2-microglobulin (β2-m) monoclonal antibody (mAb 14H3) capable of recognizing the epitope 92–99 of the protein in the monomeric native state as well as in the fibrillar polymeric state, but not in the major histocompatibility complex type I (MHCI) anchored to the cell membrane. In the present study, we investigated the molecular basis for the inaccessibility of the C-terminal end of β2-m in the MHCI complex, and demonstrated that mAb 14H3 binds the soluble fraction of the MHCI complex with a Kd of 0.3 μM. An interaction between the complex and the membrane protects β2-m from immunological recognition at the MHCI level. This protection from antibody recognition can be weakened by procedures such as heat shock or γ irradiation that perturb the membrane structure and commit the cell to the apoptotic pathway. mAb 14H3 can recognize MHCI in a transient state that most likely precedes β2-m shedding and may be proposed as a useful tool for dynamic analysis of MHCI conformational modifications. [ABSTRACT FROM AUTHOR]

An IgM lambda M-component with a false Wasserman reaction and 'false' rheumatoid factor activity from a patient suffering from a well-differentiated lymphocytic lymphoma is presented. The monoclonal protein showed antibody activity against cardiolipin and cross-reacted with acryl particles, not with human IgG. Both these activities were found in the Fab fragment. The reduction of the 19S IgM to 7S IgM subunits was responsible for a strong decrease in activity. The importance of the IgM quaternary structure in determining antibody affinity is emphasized. [ABSTRACT FROM AUTHOR]

A monoclonal IgM lambda protein from a patient (E.T.) suffering from a lymphocytic lymphoma agglutinated Salmonella typhi bacteria and uncoated acryl particles. The antigenic determinant on Salmonella typhi bacteria was found to be 0-12(α-D-Gap-(1-2)-α-D-Manp) while the structure on acryl particles recognized by IgM ET has not been defined. Both binding sites for bacteria and acryl particle determinants are localized on the same IgM molecule. The uncommon affinity of this IgM protein for some divalent heavy metal ions led to the finding of an unusually high content of sulfhydryl groups in the Fab portion of the molecule. [ABSTRACT FROM AUTHOR]

Fifteen patients with multiple myeloma, two of whom had plasma cell leukemia, were treated between May 1974 and December 1978. Peptichemio was administered intravenously at doses of 40-80 mg/48 h, courses including 4-17 administrations in association with moderate doses of prednisone (15-50 mg/day) and androstanes at high dosages (250 mg weekly). In two patients PTC was associated with vincristine (VCR) administered on the first day of the course. Eight patients were previously untreated, four had been resistant to melphalan (MPH) and/or cyclophosphamide (CTX), and three had been treated irregularly with one or both of these alkylating agents. The criteria of response to therapy are reported. Out of a total of 15 PTC courses administered we obtained 13 responses, eight complete and five partial; no response was achieved in the other two patients. In the four patients who were resistant to MPH and/or CTX we obtained three responses, which were maintained with the same alkylating agent to which they had been resistant previously. The time needed to obtain a response in 90% of the patients was 6 weeks. Peptichemio was shown to be effective in patients in an advanced stage of the disease, in patients with light-chain myeloma and in those with plasma cell leukemia. The association of VCR potentiated the antitumor effect, but also increased the myelotoxicity. The PTC treatment was well tolerated. It is suggested that PTC be used in induction treatment of myelomatosis and in patients resistant to traditional alkylating agents. [ABSTRACT FROM AUTHOR]

The clinical features and results of serological studies of a patient with Sjögren's syndrome, IgA kappa monoclonal gammopathy, and hyperviscosity syndrome are reported. The novel aspect of this case is the selective localisation to the bone marrow of lymphoplasmacytoid cells secreting IgA kappa morphologically identical to the cells infiltrating the salivary glands. The serum of the patient contained large amounts of immunoglobulin-anti-immunoglobulin immune complexes. By gel filtration chromatography it was shown that the immune complexes formed a peak of molecular weight 680 kilodaltons. The immune complexes were dissociable under acidic conditions. The immunoglobulin with rheumatoid activity was characterised as monoclonal IgA kappa protein. Treatment with plasmapheresis combined with immunosuppressive treatment with cyclophosphamide reduced the serum viscosity with concomitant clinical improvement. [ABSTRACT FROM PUBLISHER]

Peptichemio (PTC) is a mixture of six synthetic oligopeptides, each of which contains the alkylating residue m-[di(2-chloroethyl)amino]-L-phenylalanine (L-mSL). The fate of PTC was investigated in eight patients with multiple myeloma after intravenous infusion of the drug. The quantitative analysis of the plasma samples was performed by liquid chromatography with fluorometric detection. L-mSL was rapidly released from the peptides and reached its maximal plasma concentration at the end of the infusion. Its median elimination half-life was 1.73 (range, 0.72-2.41) h. It was possible to follow the concentration of only one of the peptides, L-mSL-L-Arg(NO2)-L-Nval.OEt, during and shortly after the infusion of PTC. The stability of L-mSL and the peptides was studied in buffer solution (pH 7.3), plasma, and blood. The stability of some of the peptides was drastically decreased in blood, the degradation half-lives being only about 1 min. We conclude that L-mSL plays an important role in the mechanism of action of PTC. [ABSTRACT FROM AUTHOR]