Incidence of severe knee and hip osteoarthritis in relation to different measures of body mass: a population-based prospective cohort study.

OBJECTIVE: To determine in a prospective population-based cohort study relationships between different measures of body mass and the incidence of severe knee and hip osteoarthritis defined as arthroplasty of knee or hip due to osteoarthritis. MATERIALS AND METHODS: Body mass index (BMI), waist circumference, waist-hip ratio (WHR), weight and percentage of body fat (BF%) were measured at baseline in 11,026 men and 16,934 women from the general population. The incidence of osteoarthritis over 11 years was monitored by linkage with the Swedish hospital discharge register. RESULTS: 471 individuals had knee osteoarthritis and 551 had hip osteoarthritis. After adjustment for age, sex, smoking and physical activity, the relative risks (RR) of knee osteoarthritis (fourth vs first quartile) were 8.1 (95% CI 5.3 to 12.4) for BMI, 6.7 (4.5 to 9.9) for waist circumference, 6.5 (4.6 to 9.43) for weight, 3.6 (2.6 to 5.0) for BF% and 2.2 (1.7 to 3.0) for WHR. Corresponding RR for hip osteoarthritis were 2.6 (2.0 to 3.4) for BMI, 3.0 (2.3 to 4.0) for weight, 2.5 (1.9 to 3.3) for waist, 1.3 (0.99 to 1.6) for WHR and 1.5 (1.2 to 2.0) for BF%. CONCLUSION: All measures of overweight were associated with the incidence of knee osteoarthritis, with the strongest relative risk gradient observed for BMI. The incidence of hip osteoarthritis showed smaller but significant differences between normal weight and obesity. Our results support a major link between overweight and biomechanics in increasing the risk of knee and hip osteoarthritis in men and women.

C-reactive protein, metabolic syndrome and incidence of severe hip and knee osteoarthritis. A population-based cohort study.

OBJECTIVE: To explore the relationships between C-reactive protein (CRP), metabolic syndrome (MetS) and incidence of severe knee or hip osteoarthritis (OA) in a prospective study. METHODS: A population-based cohort (n=5171, mean age 57.5+/-5.9 years) was examined between 1991 and 1994. Data was collected on lifestyle habits, measures of overweight, blood pressure as well as high-density lipoprotein (HDL) cholesterol, triglycerides, glucose and CRP measured with high-sensitive methods. Incidence of severe OA, defined as arthroplasty due to knee or hip OA, was monitored over 12 years of follow-up, in relation to CRP levels and presence of the MetS according to the adult treatment panel III-national cholesterol education program (ATPIII-NCEP) definition. RESULTS: A total of 120 participants had severe hip OA and 89 had knee OA during the follow-up. After adjustment for age, sex, smoking, physical activity and CRP, presence of MetS was associated with significantly increased risk of knee OA (relative risk [RR]: 2.1, 95% confidence interval [CI]: 1.3-3.3). However, this relationship was attenuated and non-significant after adjustment for body mass index (BMI) (RR: 1.1, 95% CI: 0.7-1.8). MetS was not significantly associated with incidence of hip OA. In women, CRP was associated with knee OA in the age-adjusted analysis. However, there was no significant relationship between CRP and incidence of knee or hip OA after risk factor adjustments. CONCLUSION: The increased incidence of knee OA in participants with the MetS was largely explained by increased BMI. CRP was not associated with incidence of knee or hip OA when possible confounding factors were taken into account.

Cutaneous delayed-type hypersensitivity reactions in smokers with chronic bronchitis and recurrent exacerbations: comparison with asymptomatic smokers and never-smokers.

The aim of the present study was to investigate whether smoking patients with chronic bronchitis (CB) and recurrent exacerbations show signs of depressed cell-mediated immunity (CMI), as reflected in the cutaneous delayed-type hypersensitivity (DTH) reaction, in comparison with asymptomatic smokers and healthy never-smokers. The study was a comparative clinical study performed at a university hospital center of respiratory medicine. Sixteen smokers with stable CB and recurrent exacerbations, five of whom had mild airflow obstruction, 18 asymptomatic smokers and 18 healthy never-smokers, all aged between 35 and 64 years, participated. No subjects treated with corticosteroids or N-acetylcysteine were included. Cutaneous DTH-reactions to seven recall antigens were assessed with Multitest, a standardized in vivo test of clinical CMI. Reactions were assessed 48 h after application by measurement of skin induration. A score (sum in mm of positive reactions) was created to assess overall reactivity. Neither the score nor the number of positive reactions differed significantly between the three study groups. Men had a significantly higher reactivity than women (P < 0.05) irrespective of group affiliation. No influence of smoking status on DTH reactivity could be seen. In the CB group no correlation was found between DTH reactivity and number of exacerbations the past 2 years. Patients with chronic bronchitis and recurrent exacerbations did not differ from asymptomatic smokers or healthy never-smokers with respect to cutaneous DTH reactions. Depression of CMI, as measured in this study, does not seem to be a primary factor behind recurrent exacerbations in smokers with CB.

Immunological findings in blood and bronchoalveolar lavage fluid in chronic bronchitis patients with recurrent infectious exacerbations.

Bronchial infections are common in smokers and seem to be related to the presence of chronic bronchitis (CB). Why only some smokers develop repeated bronchial infections is not known. The aim of this study was to screen for immunological changes associated with disease in patients with CB and recurrent infectious exacerbations compared to asymptomatic smokers. Sixteen smokers with stable CB and recurrent infectious exacerbations, and 18 asymptomatic smokers, all without any immunomodulating treatment, underwent bronchoscopy and bronchoalveolar lavage (BAL). Smoking history and current smoking status were comparable. Serum levels of immunoglobulin (Ig)A, IgM, IgG and IgG subclasses were measured. Blood and BAL lymphocyte phenotypes and proliferative responses of peripheral blood mononuclear cells (PBMCs) to various stimulators were analysed. Unstimulated and tetanus toxoid-stimulated production of cytokines in PBMC cultures was measured. Natural killer (NK-) cell activity was analysed. A significantly (p<0.05) lower level of IgG3 was found in the CB group, and a significantly (p<0.01) higher proliferative response of PBMCs was found in the CB group after stimulation with diphtheria toxoid. Detectable levels of interleukin (IL)-6, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma, but not of IL-2, IL-4 or transforming growth factor-beta2, were found in supernatants from cultured cells in both study groups. Stimulated TNF-alpha production was significantly (p<0.05) higher in the CB group. NK-cell activity did not differ significantly between the study groups. There were no major differences between the groups in lymphocyte subpopulations in blood or BAL. In conclusion, no major alterations in the analysed indices of cell-mediated and humoral immunity were found in patients with chronic bronchitis prone to recurrent infectious exacerbations when compared with asymptomatic smoking controls.

Supernatants from Staphylococcus epidermidis grown in the presence of different antibiotics induce differential release of tumor necrosis factor alpha from human monocytes.

Bacterial products from gram-positive bacteria, such as peptidoglycan, teichoic acid, and toxins, activate mononuclear cells to produce tumor necrosis factor alpha (TNF). The present study evaluated the release of soluble cell wall components from Staphylococcus epidermidis capable of inducing TNF after exposure of the bacteria to various antibiotics. A clinical S. epidermidis isolate (694) was incubated with either penicillin, oxacillin, vancomycin, or clindamycin at five times the MIC. Supernatants of the cultures obtained by filtration were added to plastic adherent monocytes in the absence or presence of human serum. After 18 h of incubation, monocyte supernatants were tested for the presence of TNF by enzyme-linked immunosorbent assay (ELISA). Supernatants from bacteria incubated with beta-lactam antibiotics induced higher TNF levels than those obtained from bacteria incubated with culture medium only (no antibiotics), vancomycin, or clindamycin. Human serum potentiated supernatant-induced TNF release, especially in beta-lactam supernatants. The soluble peptidoglycan and teichoic acid contents of supernatants, as estimated by inhibition ELISA and, for peptidoglycan, also by affinity depletion with vancomycin-Sepharose gel, were proportional to TNF release. Differences in the ability of individual antibiotics to generate TNF-releasing products from S. epidermidis were observed, the most potent antibiotics being penicillin and oxacillin.

Intracellular pathways involved in tumor necrosis factor-alpha release by human monocytes on stimulation with lipopolysaccharide or staphylococcal peptidoglycan are partly similar.

This study compared the effects of intracellular pathway inhibitors on tumor necrosis factor-alpha (TNF-alpha) release from human monocytes. Cells were stimulated with peptidoglycan (PG) from Staphylococcus epidermidis or with Escherichia coli lipopolysaccharide (LPS), both in the presence of 10% human serum. Of 10 substances tested, only the protein tyrosine kinase inhibitor tyrphostin AG 126 discriminated significantly between PG and LPS: TNF-alpha release induced by PG, but not by LPS, was dose-dependently suppressed. The results obtained with other modulatory substances, including different protein kinase and G protein inhibitors, suggest that calmodulin-dependent protein kinase, protein tyrosine kinase, and a cholera-toxin-sensitive G protein are involved in both PG- and LPS-induced TNF-alpha release. Further, drugs such as pentoxifylline, chloroquine, and the antioxidant apocynin similarly inhibited TNF-alpha release by PG- as well as LPS-stimulated cells.

Comparative antibacterial activity of L-695,256, a carbapenem active against methicillin-resistant staphylococci.

The activity of a new prototype carbapenem, L-695,256, against clinical isolates of gram-positive and gram-negative aerobes was studied in vitro by agar dilution. L-695,256 was highly active against methicillin-resistant and -susceptible isolates of staphylococci (MICs, 0.016 to 2 micrograms/ml) and against penicillin-resistant pneumococci (MICs, 0.016 to 0.064 micrograms/ml), irrespective of penicillin susceptibility. Activity against members of the family Enterobacteriaceae was less than that of imipenem, while Proteus mirabilis and Morganella morganii were more susceptible to L-695,256.

Serum-induced potentiation of tumor necrosis factor alpha production by human monocytes in response to staphylococcal peptidoglycan: involvement of different serum factors.

Peptidoglycan from a Staphylococcus epidermidis strain, isolated from a patient with septicemia, was preincubated with human serum. This mixture was then investigated for its potency to induce tumor necrosis factor (TNF) secretion by human blood monocytes. TNF was measured in the supernatants by using a bioassay and/or an enzyme-linked immunosorbent assay specific for TNF alpha (TNF-alpha). Although earlier studies indicated that staphylococcal peptidoglycan alone is a relatively poor stimulator of TNF-alpha production, the present study shows that human serum highly potentiates peptidoglycan-induced TNF-alpha release by human monocytes. In the presence of serum and in the low-dose range, peptidoglycan was almost as potent as endotoxin. At high peptidoglycan concentrations, monocytes showed an extremely high TNF-alpha response, but again only in the presence of serum. At low peptidoglycan doses, the stimulatory effect of serum was abrogated by heat treatment or depleting serum of complement components C1 and C3/C4, which suggests a role for the classical complement pathway. At high doses of peptidoglycan, the serum stimulatory effect depended mainly on immunoglobulin G.

Analysis of immunoglobulin isotype levels in acute pneumococcal bacteremia and in convalescence.

In 48 patients with a history of a pneumococcal bacteremia, serum taken during the acute phase of the infection was analyzed for IgG and IgG subclasses. Once the patients were free of infection, a serum sample was analyzed for IgG, IgG subclasses, IgA and IgM. In an additional 20 patients, it was only possible to analyze serum from the infection-free phase. Seventeen of 48 (35%) patients had reduced levels of total IgG or of one or more of the IgG subclasses during acute disease. Of the 48 patients in whom both acute phase and infection-free phase serum were analyzed, values of IgG (p < 0.001), IgG1 (p < 0.001), IgG2 (p < 0.001), IgG3 (p < 0.01) and IgG4 (p < 0.01) were decreased during the acute infection. During the infection-free phase, 12 of 68 (18%) patients had a recognizable immunodeficiency, including two patients with common variable immunodeficiency. Routine screening for immunoglobulins during the infection-free period could result in the discovery of previously unrecognized immunoglobulin deficiencies in patients with a history of bacteremic pneumococcal infection.

Peptidoglycan and teichoic acid from Staphylococcus epidermidis stimulate human monocytes to release tumour necrosis factor-alpha, interleukin-1 beta and interleukin-6.

Cytokines play a major role in the pathophysiology of septic shock. In this study, human peripheral blood monocytes were stimulated with peptidoglycan and teichoic acid, purified from a strain of Staphylococcus epidermidis. Polymyxin B (PM-B) was added to avoid the effects of possible contamination with endotoxin. Tumour necrosis factor-alpha (TNF), interleukin-1 beta (IL-1), and interleukin-6 (IL-6) in the supernates were measured by enzyme-linked immunosorbent assays. Peptidoglycan and teichoic acid induced TNF, IL-1, and IL-6 in a concentration-dependent manner. Teichoic acid was a weaker inducer than peptidoglycan, especially for IL-1. Lipopolysaccharide from an E. coli strain was used as a control, being 100-1000 times more potent than peptidoglycan and teichoic acid.

Neurologic adverse effects during concomitant treatment with ciprofloxacin, NSAIDS, and chloroquine: possible drug interaction.

OBJECTIVE: To report a case of neurologic adverse effects that developed during concomitant treatment with ciprofloxacin, nonsteroidal antiinflammatory drugs (NSAIDs), and chloroquine. Possible mechanisms for a drug interaction are discussed. CASE SUMMARY: A 68-year-old woman who was receiving chronic treatment with NSAIDs and chloroquine developed dizziness, anxiety, and tremors when ciprofloxacin 500 mg twice daily was begun for Salmonella osteitis. When she discontinued the antirheumatic treatment, there was a prompt relief of symptoms. After indomethacin was reintroduced, the patient developed signs and symptoms of peripheral neuropathy, which partially subsided when ciprofloxacin was discontinued. DISCUSSION: Enhanced neurologic adverse effects of ciprofloxacin when taken together with NSAIDs or chloroquine may result from reduced effects of gamma-aminobutyric acid. An alternative explanation could be that NSAIDs and chloroquine impair the elimination of ciprofloxacin, thereby contributing to toxic concentrations of the antibiotic. CONCLUSIONS: The possibility of interactions between ciprofloxacin and antirheumatic drugs should be considered.

Bronchoscopic diagnosis of pulmonary infections in a heterogeneous, nonselected group of patients.

Fiberoptic bronchoscopy with bronchoalveolar lavage and protected specimen brush technique has become an established method for etiologic diagnosis in severe forms of pulmonary infections during recent years. In this study, including 62 bronchoscopies in 53 patients, a standardized program, covering all important pulmonary pathogens, has been evaluated in a heterogeneous group of patients. Results providing therapeutic guidelines were obtained in 53 percent (16/30) of the immunocompromised patients (including 5 bronchoscopies on HIV-positive patients), but only 19 percent (6/32) of the immunocompetent patients (p < 0.001). We conclude that bronchoscopy is of great value for diagnosing pulmonary infections in immunocompromised patients. In immunocompetent patients, the diagnostic yield is lower and the indication for bronchoscopy must be established for each individual patient based on clinical importance, resources, and risk. When bronchoscopy is performed, we believe that a standardized program like ours reduces the risk of missing important pathogens.

Characterization and distribution of Pasteurella species recovered from infected humans.

During a 3-year period, all Pasteurella strains recovered at the Clinical Microbiological Laboratory, Lund, Sweden, were studied biochemically with respect to their relationship to the recently described taxa of this genus. Of 159 strains recovered from 146 infected humans, 95 were identified as Pasteurella multocida subsp. multocida, 21 as Pasteurella multocida subsp. septica, 28 as Pasteurella canis, 10 as Pasteurella stomatis, and 5 as Pasteurella dagmatis. The homology within and between the Pasteurella species regarding cellular fatty acids and enzymatic activities was also studied. Strains of the different Pasteurella species were indistinguishable from each other regarding fatty acid composition; all strains contained major amounts of C14:0, C16:1, C16:0, and 3-OH-C14:0 acids and minor amounts of C18:2, C18:1, and C18:0 acids. Neither did the enzymatic activities distinguish between strains belonging to different species. In addition, of 56 strains examined, toxin production was demonstrated only in 1 strain each of P. multocida subsp. multocida and P. canis. Except for one severe case of necrotizing cellulitis involving P. dagmatis, P. multocida subsp. multocida or P. multocida subsp. septica was recovered in the more serious cases of infection. Except for P. canis, which in all cases was associated with dog bites, most Pasteurella strains were recovered in cases of infection associated with cat bites or scratches. Pasteurella strains occurred in four infected patients without evident connections with animals.

In vivo processing of Staphylococcus aureus lipase.

The Staphylococcus aureus lipase gene encodes a 76-kDa protein. Extracellular lipase purified from culture supernatants is only 45 to 46 kDa, however. We show that the lipase is secreted in vivo as an 82-kDa protein with full enzymatic activity. It is then sequentially processed, both in culture and in cell-free supernatants, to a mature, 45- to 46-kDa protein. Protein sequencing demonstrates that the N-terminal region of the 82-kDa prolipase, comprising 295 amino acids, is cleaved from the central and C-terminal moieties, which contain the active site. A metallocysteine protease is probably responsible for initiating this processing. The extremely hydrophobic, mature lipase is resistant to further protease degradation and retains the full catalytic activity of the prolipase.

Aggregation of human granulocytes by Staphylococcus aureus lipase.

The effects of purified extracellular lipase from Staphylococcus aureus on human granulocytes were studied in vitro with a turbidimetric technique. Within the concentration range 0.6-4.4 micrograms/ml, lipase caused monophasic aggregation accompanied by the release of lactoferrin; the corresponding concentrations of the solvent in which it was suspended, Triton X100, had no effect. Lipase-induced aggregation did not occur in the presence of autologous plasma.

Antibody response to Staphylococcus aureus whole cell, lipase and staphylolysin in patients with S. aureus infections.

Three assays to measure antibodies against Staphylococcus aureus whole cells, lipase and staphylolysin were used to try to discriminate between complicated and uncomplicated S. aureus septicaemia. Sera were examined from 8 patients with S. aureus endocarditis, 23 patients with complicated S. aureus septicaemia, 12 patients with uncomplicated S. aureus septicaemia and 93 febrile non-septicaemic controls. No single assay could distinguish between complicated and uncomplicated S. aureus septicaemia. If the criterion for a positive result is defined as positive antibody level in the anti-lipase ELISA as well as in at least 1 of the other 2 assays, 10/31 patients with S. aureus endocarditis or complicated septicaemia were positive compared to 0/93 non-septicaemic patients and 0/12 patients with uncomplicated S. aureus septicaemia. Therefore, the combined use of serological assays in the diagnosis of complicated S. aureus septicaemia, one of which is the anti-lipase ELISA, is recommended.