The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: a randomised controlled trial.

OBJECTIVE: Epidemiological data suggest low serum 25-hydroxyvitamin D3 (25-OH-D3) levels are associated with radiological progression of knee osteoarthritis (OA). This study aimed to assess whether vitamin D supplementation can slow the rate of progression. METHOD: A 3-year, double-blind, randomised, placebo-controlled trial of 474 patients aged over 50 with radiographically evident knee OA comparing 800 IU cholecalciferol daily with placebo. Primary outcome was difference in rate of medial joint space narrowing (JSN). Secondary outcomes included lateral JSN, Kellgren & Lawrence grade, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function, stiffness and the Get up and Go test. RESULTS: Vitamin D supplementation increased 25-OH-D3 from an average of 20.7 (standard deviation (SD) 8.9) µg/L to 30.4 (SD 7.7) µg/L, compared to 20.7 (SD 8.1) µg/L and 20.3 (SD 8.1) µg/L in the placebo group. There was no significant difference in the rate of JSN over 3 years in the medial compartment of the index knee between the treatment group (average -0.01 mm/year) and placebo group (-0.08 mm/year), average difference 0.08 mm/year (95% confidence interval (CI) [-0.14-0.29], P = 0.49). No significant interaction was found between baseline vitamin D levels and treatment effect. There were no significant differences for any of the secondary outcome measures. CONCLUSION: Vitamin D supplementation did not slow the rate of JSN or lead to reduced pain, stiffness or functional loss over a 3-year period. On the basis of these findings we consider that vitamin D supplementation has no role in the management of knee OA.

Genotypic and phenotypic properties of coagulase-negative staphylococci causing dialysis catheter-related sepsis.

Sixty coagulase-negative staphylococcus (CNS) isolates were recovered from the blood cultures or peritoneal dialysate effluent of 43 patients on renal dialysis. The patients had either renal dialysis catheter-related sepsis (CRS) or continuous ambulatory peritoneal dialysis (CAPD)-associated peritonitis. Isolates were characterized by biotyping, and genotyped by pulsed-field gel electrophoresis (PFGE). Phenotypic properties of the strains were also investigated. Several genotypes were identified with no one specific strain of CNS being associated with CRS. However, closely related strains were isolated from several patients within the units studied, suggesting horizontal transfer of micro-organisms. Genotypic macro-restriction profiles did not concur with phenotypic profiles or biotypes, confirming that genotyping is required for epidemiological studies. All staphylococcal strains were investigated for the production of phenotypic characteristics. Significant differences were predominantly seen in the production of lipase, esterase and elastase in strains isolated from the renal patients with CRS and CAPD-associated peritonitis, compared with a non-septic control group. These phenotypic characteristics may therefore have a role in the maintenance of CRS in renal patients.

The influence of hemodynamic stress factors on intracranial aneurysm formation.

OBJECT: Applanation tonometry is a noninvasive method of assessing both peripheral and central arterial blood pressure (BP) profiles. In this study the authors examine whether there are differences in these profiles in patients with intracranial aneurysms when compared with age-matched controls. METHODS: Carotid artery (CA) and derived aortic BP waveforms were obtained using a pulse wave analysis system. The ratio of the pressure wave amplitude above the systolic shoulder to the total systolic BP (augmentation index [AI]) was recorded. One hundred seventy-three patients with intracranial aneurysms (23 unruptured lesions) and 173 healthy control volunteers were examined. For the patients with aneurysms the right and left CA AIs (mean +/- standard deviation) were 125.6 +/- 23.1% and 128.3 +/- 22.1%, respectively. Corresponding values for the control group were 118.4 +/- 22.6% and 119.4 +/- 21.8%. The calculated AI for the ascending aorta was 29.8 +/- 10.5% and 25.6 +/- 12.2% for patients with aneurysms and control volunteers, respectively. Significant asymmetry in CA AI was seen in patients with aneurysms, the left being greater (p = 0.002). No significant differences were seen in mean BP (108 +/- 14 mm Hg in patients with aneurysms compared with 106 +/- 16 mm Hg in controls; p = 0.2). Multivariate analysis excluded the influence of BP and other potential confounding vascular risk factors for increased AI. CONCLUSIONS: Significant differences in AI, both in magnitude and symmetry, were identified in patients with intracranial aneurysms when compared with matched controls.

Rapid serodiagnosis of gram-positive bacterial endocarditis.

OBJECTIVES: To characterize a serological test for diagnosing endocarditis caused by Gram-positive cocci. METHODS: We have developed an indirect enzyme-linked immunosorbent assay (ELISA) for the serological detection of Gram-positive infections. The test measures serum IgG directed towards lipid S, a recently identified exocellular glycolipid antigen which is related to lipoteichoic acid. We have previously shown the test to be of value in serodiagnosis of central venous catheter-associated sepsis and infection of orthopaedic prostheses caused by coagulase-negative staphylococci. We now describe the application of this test in endocarditis. RESULTS: Serum IgG levels to lipid S were significantly elevated in 34 patients with Gram-positive bacterial endocarditis confirmed as 'definite' by the Duke criteria as compared to 50 control patients. The test had a sensitivity of 88% and a specificity of 88%. CONCLUSIONS: The assay is independent of culture results or endocardial imaging, making it complementary to currently used investigations. It may therefore be possible to refine the current Duke criteria for diagnosing endocarditis. We describe an algorithm which incorporates lipid S serology into a positive diagnostic strategy.

Serological detection of Gram-positive bacterial infection around prostheses.

Coagulase-negative staphylococci produce an exocellular glycolipid antigen which has potential as a serological marker of infection in bone. The value of this newly detected antigen was investigated by enzyme-linked immunosorbent assay (ELISA) in 15 patients with culture-proven infection of prostheses caused by Gram-positive bacteria. The antigen was purified by gel-permeation chromatography from the culture supernatants of coagulase-negative staphylococci grown in a chemically defined medium. There were significant differences (p < 0.0001) between the serum IgG and IgM levels in patients with infection due to Gram-positive staphylococci and those of a control group of 32 patients with no infection. The ELISA test, which has potential for the diagnosis of infection, may be valuable in distinguishing between staphylococcal infection around prostheses and aseptic loosening.

Lipid S, a novel Staphylococcus epidermidis exocellular antigen with potential for the serodiagnosis of infections.

We describe the characterisation of a novel glycerophosphoglycolipid (termed lipid S) produced by Staphylococcus epidermidis grown in a chemically defined medium. Lipid S is a short chain length form of the cellular lipoteichoic acid (LTA). It shares common antigenic determinants with LTA, but its chain length of six glycerophosphate units contrasts with 40-42 units in LTA. Lipid S is exocellular and can be recovered from liquid growth medium whereas LTA is associated with the cell wall and membrane. Healthy individuals have low serum levels of IgG against lipid S, but significantly higher titres have been detected in serum from patients with central venous catheter-related sepsis due to coagulase-negative staphylococci and infection of orthopaedic prostheses. An indirect enzyme-linked immunosorbent assay test based on lipid S allows the rapid diagnosis of Gram-positive infection and may have clinical applications in the management of patients with sepsis.

A central venous catheter coated with benzalkonium chloride for the prevention of catheter-related microbial colonization.

In an attempt to overcome infections associated with central venous catheters, a new antiseptic central venous catheter coated with benzalkonium chloride on the internal and external surfaces has been developed and evaluated in a clinical trial. Patients (235) randomly received either a triple-lumen central venous catheter coated with benzalkonium chloride (117) or a polyurethane non-antiseptic catheter (118). The incidence of microbial colonization of both catheters and retained antiseptic activity of the benzalkonium chloride device following removal were determined. The benzalkonium chloride resulted in a significant reduction of the incidence of microbial colonization on both the internal and external catheter surfaces. The reduction in colonization was detected at both the intradermal (21 benzalkonium chloride catheters vs. 38 controls, P = 0.0016) and distal segments of the antiseptic-coated catheters. Following catheter removal retained activity was demonstrated in benzalkonium chloride catheters which had been in place for up to 12 days. No patients developed adverse reactions to the benzalkonium chloride catheters. The findings demonstrate that the benzalkonium chloride catheter significantly reduced the incidence of catheter-associated colonization.

A novel serological test for the diagnosis of central venous catheter-associated sepsis.

OBJECTIVES: To determine the sensitivity and specificity of a novel antibody test for the diagnosis of intravascular catheter-related infections due to coagulase-negative staphylococci. METHODS: Sixty-seven patients diagnosed as having central venous catheter (CVC)-associated sepsis based on strict clinical criteria, including positive blood cultures, were compared to 67 patients with a CVC in situ who exhibited no evidence of sepsis. An ELISA serological test based on a novel short-chain lipoteichoic acid antigen isolated from coagulase-negative staphylococci (CNS) was used to determine the patient's serological response (IgG and IgM) to CVC sepsis caused by CNS. The specificity and sensitivity of the test was determined. RESULTS: There was a significant increase in the antibody levels (IgG and IgM) to the short-chain lipoteichoic acid in patients with CVC-associated staphylococcal sepsis as compared to the control patients. CONCLUSIONS: This new serological method may offer a useful diagnostic test for intravascular catheter infections caused by staphylococci.

The ACE I allele is associated with increased risk for ruptured intracranial aneurysms.

Genetic and environmental factors play roles in the aetiology of ruptured intracranial aneurysms. Hypertension has been reported as a risk factor for intracranial aneurysm haemorrhage. We have tested if genotypes at the angiotensin converting enzyme (ACE) gene locus are associated with ruptured intracranial aneurysms. The insertion/deletion polymorphism in the ACE gene was genotyped in 258 subjects presenting in East Anglia with ruptured intracranial aneurysms (confirmed at surgery or angiographically) and 299 controls from the same region. ACE allele frequencies were significantly different in the cases and the controls (alleles chi(2)(1)=4.67, p=0.03). The I allele was associated with aneurysm risk (odds ratio for I allele v D allele = 1.3 (95% CI=1.02-1-65); odds ratio for II v DD genotype = 1.67 (95% CI=1.04-2.66)). The I allele at the ACE locus is over-represented in subjects with ruptured intracranial aneurysms. These data are supported by non-significant trends in the same direction in two previous smaller studies. Thus, this allele may be associated with risk for ruptured intracranial aneurysms.

A prospective clinical study to investigate the microbial contamination ofa needleless connector.

Needleless connectors, which allow direct access to intravascular catheters, are widely used in clinical practice. The benefits of these devices to healthcare workers are well documented; however, the potential risk of microbial contamination and associated infection is unclear. This clinical study evaluated microbial contamination rates for a needleless connector, Connecta Clave(R) (CC(R)), as compared to a conventional three-way tap, which was connected to the hubs of central venous catheters (CVC) immediately following insertion. Patients in the study group had CC(R) attached to the three-way taps, whereas the control group had standard entry port caps. On removal (up to 72 h) the connectors were studied for microbial contamination. There was no significant difference between the number of three-way taps contaminated on the internal surface with micro-organisms in the control group with entry port caps (19/132, 14%) compared to the group with CC(R) (18/105, 17%). Sixteen percent (27/173) of the CC(R) were contaminated with micro-organisms on the internal surfaces. The external surface of 33% (27/82) of the CC(R) silicone seals were contaminated after clinical use. Micro-organisms were also isolated from 9% (8/91) of the silicone seals after disinfection. The use of this needleless connector, compared to standard caps therefore does not appear to increase the risk of infection via the internal lumen of three-way taps.

Interferential therapy machines as possible vehicles for cross-infection.

Interferential therapy machines are used to apply alternating electric currents to patients for the treatment of various musculo-skeletal complaints. The potential for such machines to transfer skin microflora from one patient to another during treatment was investigated. The efficacy of the current disinfection procedure of the machines was also evaluated. In both the laboratory and clinical situation, interferential treatment, (which involves the direct application of electrodes to the skin surface) resulted in the transfer of micro-organisms from the skin of one subject to another. To decrease the likelihood of transmission of micro-organisms via interferential therapy machines, it is recommended that both the suction cups and sponges are disinfected with 70% isopropyl alcohol after the treatment of each patient. The use of disposable electrodes could also be considered.

Prevention of central venous catheter-related infection.

Infections associated with central venous catheters continue to be a major source of sepsis, particularly in hospitalized patients. In developing a strategy for the prevention of these infections, the source and route of invasion of the causative micro-organisms need to be considered. The main source of micro-organisms is the patient's skin. They can gain access to a catheter at the time of insertion, as well as via the external or internal catheter surfaces. Attempts to reduce the incidence of infections range from the type of skin preparation selected, to care of the insertion site post-catheterization. Improvements in catheter design have also reduced the likelihood of infection and include the development of non-leachable smooth catheters with anti-adhesive coatings. More recently, catheters containing antimicrobial agents have become available and preliminary studies have demonstrated a reduction in microbial colonization and associated sepsis. Future preventative strategies may include the application of low voltage electric current in combination with antimicrobials.

Role of antimicrobial-impregnated polymer and Teflon in the prevention of biliary stent blockage.

Biliary stent blockage and microbial colonization is a common complication associated with polyurethane stents used for the relief of bile-duct obstruction caused by benign or malignant disease. In an attempt to overcome this problem the application of a 'Teflon' (polytetrafluoroethylene) stent and an antimicrobial benzalkonium chloride (BZC) impregnated polymer were investigated. The effects of these materials on microbial colonization were compared to a polyurethane stent in vitro in broth or bile. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of BZC for three commonly isolated biliary stent pathogens, Staphylococcus epidermidis, Enterococcus faecium and Enterobacter cloacae were also determined. All the isolates were sensitive to BZC. The growth kinetics of the three organisms in broth and in human pooled bile were similar. Adherence to the BZC impregnated polymer was significantly reduced as compared to the polyurethane and Teflon stents (P < 0.05) in nutrient broth. In bile, fewer organisms attached to the Teflon as compared with the polyurethane stent (P < 0.05) for all organisms. For two of the three test organisms there was less bacterial adherence to the Teflon than to the BZC impregnated polymer. The Teflon and antimicrobial stent materials studied may prevent biliary stent blockage resulting from microbial colonization.

Use of pulsed field gel electrophoresis to determine the source of microbial contamination of central venous catheters.

Microorganisms detected in situ on the distal tip of central venous catheters (CVC) within 90 min of insertion were investigated using pulsed-field gel electrophoresis to analyse genomic fragments obtained with the SmaI restriction enzyme. Thirty patients received a triple lumen CVC, which was inserted directly through the skin using the Seldinger technique. In a further 30 patients a triple lumen CVC was inserted through a Swan sheath, thereby avoiding direct contact of the CVC with the skin. Staphylococci were isolated from the distal tips of the catheters in 6 patients (5 who had the CVC inserted directly through the skin and 1 who had the CVC inserted via a Swan sheath.) Twenty-three staphylococcal isolates were also isolated from the insertion equipment and the skin swabs surrounding the insertion site of these six patients. All the isolates were genotyped. In one of the patients the organisms isolated from the skin were identical to those on the CVC tip. In two further patients similar organisms were isolated from the insertion equipment and the patients' skin. These results, in addition to the reduced colonisation rates observed when catheters were introduced through a Swan sheath, support the hypothesis that microorganisms from the skin are impacted onto the CVC tip and the CVC insertion equipment at catheter insertion.

Evaluation of the in-vitro activity of the glycopeptide antibiotic LY333328 in comparison with vancomycin and teicoplanin.

The in-vitro activity of a new glycopeptide antibiotic, LY333328, was compared with vancomycin and teicoplanin against clinical isolates of Staphylococcus aureus, coagulase-negative staphylococci, vancomycin and teicoplanin resistant enterococci, and vancomycin sensitive and resistant enterococci. MIC, MBC, and time-kill kinetics were determined for each agent. LY333328 displayed similar or improved MIC/MBC values in comparison with vancomycin and teicoplanin. Time-kill kinetics for LY333328 demonstrated significantly improved bactericidal activity against the isolates. These findings suggest that LY333328 has improved in-vitro activity over vancomycin and teicoplanin against a range of gram-positive organisms.

Novel approach to investigate a source of microbial contamination of central venous catheters.

The potential route of contamination by skin microorganisms onto the distal tip of central venous catheters during insertion was investigated. Thirty patients undergoing cardiac surgery who required a central venous catheter (CVC) as part of their clinical management were studied. Following catheter placement, the device insertion equipment and the skin at the insertion site were sampled for microorganisms. The distal tips of the CVCs were also sampled in situ within 90 min post insertion. Bacteria were isolated from 20 of 30 (66%) CVC skin insertion sites, from 15 of 30 (50%) guidewires, and from five of 30 (16%) catheter distal tips in situ. These findings suggest that despite rigorous skin disinfection and strict aseptic technique, viable microorganisms are impacted during insertion onto the distal tip of the CVC, which may act as a subsequent nidus of infection.

Do dressings with increased permeability reduce the incidence of central venous catheter related sepsis?

The incidence of catheter-related sepsis associated-with the use of Tegaderm or Opsite IV3000 dressings on 100 critically ill patients with liver disease was studied. All the patients had central venous catheters in situ and they were randomly assigned to one of the two dressings. In this study the sites of insertion were assessed at each dressing change, together with any fluid under the dressing. No statistically significant difference between the two dressings was found in accumulation of fluid, skin microbial colonization, local infection or systemic infection of patients in our sample. There was no apparent advantage to using the more permeable Opsite IV3000 dressing.