How safe are gloves and masks used for protection against Legionella longbeachae infection when gardening?

Legionella longbeachae has been frequently identified in composted plant material and can cause Legionnaires' disease (LD). We wanted to determine how frequently L. longbeachae DNA was present on gardeners' gloves, and how long L. longbeachae could persist on inoculated gloves and masks. Volunteers completed a survey of gardening practices and their gardening gloves were tested for L. longbeachae DNA by qPCR. The persistence of viable L. longbeachae was assessed by timed subcultures after inoculation of gardening gloves and masks. Gloves but not masks were used regularly. L. longbeachae was detected on 11 (14%; 95% CI 8-24%) gloves. Viable organisms were recovered from 25-50% of inoculated cotton, leather and PU coated gloves but not rubber gloves after 8 h incubation. There was a difference in dose-response curve slopes by glove material (P = 0·001) and time to 50% sterility (P = 0·036). There were differences in persistence of L. longbeachae between mask types from analysis of the slopes and 50% sterility on the decay curves (P = 0·042, P < 0·001 respectively). Gardening gloves and masks may act as a vector for transmission of L. longbeachae during gardening. Washing gardening gloves and prompt disposal of masks could reduce risk of LD.

Cystathionine-γ-lyase gene silencing with siRNA in monocytes/ macrophages attenuates inflammation in cecal ligation and puncture-induced sepsis in the mouse.

Hydrogen sulphide is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in macrophages. To determine the role of H2S and macrophages in sepsis, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of sepsis. Cecal ligation puncture (CLP)-induced sepsis is characterized by increased levels of myeloperoxidase (MPO) activity, morphological changes in liver and pro-inflammatory cytokines and chemokines in the liver and lung. SiRNA treatment attenuated inflammation in the liver and lungs of mice following CLP-induced sepsis. Liver MPO activity increased in CLP-induced sepsis and treatment with siRNA significantly reduced this. Similarly, lung MPO activity increased following induction of sepsis with CLP while siRNA treatment significantly reduced MPO activity. Liver and lung cytokine and chemokine levels in CLP-induced sepsis reduced following treatment with siRNA. These findings show a crucial pro-inflammatory role for H2S synthesized by CSE in macrophages in sepsis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.

Cystathionine-gamma-lyase gene silencing with siRNA in monocytes/macrophages protects mice against acute pancreatitis.

Hydrogen sulphide (H2S) is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in monocytes/macrophages. To determine the role of H2S and macrophages in inflammation, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of acute pancreatitis. Acute pancreatitis is characterised by increased levels of plasma amylase, myeloperoxidase (MPO) activity and pro-inflammatory cytokines and chemokines in the pancreas and lung. SiRNA treatment attenuated inflammation in the pancreas and lungs of mice following caerulein-induced acute pancreatitis. MPO activity increased in caerulein-induced acute pancreatitis (16.21 ± 3.571 SD fold increase over control) and treatment with siRNA significantly reduced this (mean 3.555 ± 2.522 SD fold increase over control) (p < 0.0001). Similarly, lung MPO activity increased following treatment with caerulein (3.56 ± 0.941 SD fold increase over control) while siRNA treatment significantly reduced MPO activity (0.8243 ± 0.4353 SD fold increase over control) (p < 0.0001). Caerulein treatment increased plasma amylase activity (7094 ± 207 U/l) and this significantly decreased following siRNA administration (5895 ± 115 U/l) (p < 0.0001). Cytokine and chemokine levels in caerulein-induced acute pancreatitis reduced following treatment with siRNA. For example, siRNA treatment significantly decreased pancreatic and lung monocyte chemoattractant protein (MCP)-1 (169.8 ± 59.75 SD; 90.01 ± 46.97 SD pg/ml, respectively) compared to caerulein-treated mice (324.7 ± 103.9 SD; 222.8 ± 85.37 SD pg/ml, pancreas and lun,g respectively) (p < 0.0001). These findings show a crucial pro-inflammatory role for H2S synthesised by CSE in macrophages in acute pancreatitis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.

Consensus guidelines for the treatment of invasive mould infections in haematological malignancy and haemopoietic stem cell transplantation, 2014.

Mould species represent the pathogens most commonly associated with invasive fungal disease in patients with haematological malignancies and patients of haemopoietic stem cell transplants. Invasive mould infections in these patient populations, particularly in the setting of neutropenia, are associated with high morbidity and mortality, and significantly increase the complexity of management. While Aspergillus species remain the most prevalent cause of invasive mould infections, Scedosporium and Fusarium species and the Mucormycetes continue to place a significant burden on the immunocompromised host. Evidence also suggests that infections caused by rare and emerging pathogens are increasing within the setting of broad-spectrum antifungal prophylaxis and improved survival times placing immunosuppressed patients at risk for longer. These guidelines present evidence-based recommendations for the antifungal management of common, rare and emerging mould infections in both adult and paediatric populations. Where relevant, the role of surgery, adjunctive therapy and immunotherapy is also discussed.

Effect of vitamin D3 supplementation on Staphylococcus aureus nasal carriage: a randomized, double-blind, placebo-controlled trial in healthy adults.

Observational studies have reported an inverse association between serum 25-hydroxyvitamin D (25OHD) concentrations and Staphylococcus aureus nasal carriage; however, clinical trials of vitamin D supplementation are lacking. To assess the effect of vitamin D3 supplementation on persistent S. aureus nasal carriage we conducted a randomized, double-blind, placebo-controlled trial among 322 healthy adults. Participants were given an oral dose of either 200 000 IU vitamin D3 for each of 2 months, followed by 100 000 IU monthly or placebo in an identical dosing regimen, for a total of 18 months. Nasal swabs for S. aureus culture and serum for 25OHD measurement were obtained at baseline, 6, 12 and 18 months of study. The mean baseline concentration of 25OHD was 72 nM (SD 22 nM). Vitamin D3 supplementation increased 25OHD levels which were maintained at >120 nM throughout the study. Nasal colonization by S. aureus was found in 31% of participants at baseline. Persistent carriage, defined as those that had positive S. aureus nasal cultures for all post-baseline swabs, occurred in 20% of the participants but vitamin D3 supplementation was not associated with a reduction in persistent carriage (OR = 1.39, 95% CI 0.63-3.06). Risk factor analysis showed that only gender was significantly associated with carriage, where women were less likely to be carriers than men (relative risk 0.83, 95% CI 0.54-0.99). Serum 25OHD concentrations were not associated with the risk of carriage. In conclusion, monthly administration of 100 000 IU of vitamin D3 did not reduce persistent S. aureus nasal carriage.

Outcomes of infected abdominal aortic grafts managed with antimicrobial therapy and graft retention in an unselected cohort.

OBJECTIVE: To document the treatment of all patients with infected aortic grafts at Christchurch Hospital between 1999 and 2010, focussing on the mortality and morbidity of those treated without graft explantation. METHODS: Cases of infected aortic grafts were reviewed. Cases required a compatible clinical syndrome, CT imaging and tissue/blood culture results. RESULTS: Eighteen patients were identified. Organisms isolated at diagnosis from blood or graft site were Staphylococcus aureus 6 (MRSA 1), beta haemolytic streptococci 2, enteric organisms 9.There was no isolate from 2. One case had graft explantation and brief antimicrobial therapy. Seventeen patients had the graft retained. Of these, 14 received intravenous antimicrobial therapy for 6 weeks and 14 lifelong oral therapy. None died during their initial admission or within 30 days. During a mean follow-up of 57 months, 10 (59%) relapsed (median time 31 months, range 0--98), 4 (24%) underwent graft explantation and 10 (59%) died (median 40 months, range 1e 198). Four of 10 who relapsed had organisms isolated (all enteric). CONCLUSION: Patients treated with lifelong antimicrobial therapy and graft retention survived a median of 41 months, with low early mortality although over half relapsed. Empiric therapy should cover skin organisms and enteric organisms, even for those outside the post-operative period.

Population-based epidemiology of Staphylococcus aureus bloodstream infection in Canterbury, New Zealand.

BACKGROUND: Few contemporary reports describe population-based incidence of Staphylcoccus aureus bloodstream infection (SABSI). AIM: To describe longitudinal incidence of SABSI in a region of New Zealand with low MRSA prevalence. METHODS: Blood cultures growing S. aureus were identified from hospital laboratories between 1 July 1998 and 30 June 2006. Record linkage was used to combine information from local and national databases into a single patient event record. Information from the New Zealand census was used to determine regional incidence of disease. An address-based measure of deprivation was used to analyse the relationship between incidence and socioeconomic status. Morbidity data were not collected. RESULTS: 779 patients with SABSI were identified (482/779 (62%) male, 297/779 (38%) female). The crude incidence of S. aureus bacteraemia varied between 18.5-27.3/100 000 per annum. Three of 779 isolates (0.4%) were MRSA. Two hundred and seventy-seven of 776 (36%) patients with complete records had hospital-acquired SABSI. One hundred and forty-one of 778 patients (18%) died within 30 days and 235/778 (30%) died within a year. Proportional hazards survival models significantly associated age, male sex and more than 14 days of hospitalization in the year prior to index culture with adverse outcome. Higher socioeconomic status was associated with lower rates of SABSI (adjusted rate ratio 0.74, 95% confidence interval: 0.56-0.98, P= 0.007 after adjustment for age and sex, and comparing the highest and lowest deprivation quintiles). CONCLUSION: Population factors significantly influence SABSI incidence and survival. Further research is required to determine whether these have the potential to invalidate inter-hospital comparison of SABSI incidence as a measure of health-care quality.

Dietary and supplementary betaine: effects on betaine and homocysteine concentrations in males.

BACKGROUND AND AIMS: Betaine is an osmolyte that when catabolised decreases plasma total homocysteine. A betaine-rich meal has acute effects similar to a supplement, but the effects of a longer-term increase in dietary betaine intake need clarification. We compared the effects of two weeks of dietary and supplementary betaine on plasma betaine and homocysteine concentrations both fasting and after a methionine load. METHODS AND RESULTS: In a randomized crossover study, 8 healthy males (22-36 y) consumed either a betaine-rich diet ( approximately 800 mg/day) or a betaine supplement (0.5 g twice daily) for 14 days. Fasting blood samples were collected on day -5, -1 (pre-treatment) 0, 2, 6, 9, 13 (treatment), 14 and 18 (post-treatment). Post-methionine load blood samples were collected on day -5, 0, 6 and 13, while 24h urine samples were collected on day -5, 0, 6, 13 and 14. Plasma betaine, dimethylglycine, homocysteine and urine betaine, dimethylglycine and creatinine concentrations were measured. Plasma betaine concentrations significantly increased for both treatments compared to pre-treatment values (P<0.001). Fasting homocysteine levels were minimally affected. Both treatments reduced post-methionine load homocysteine and this effect tended to be greater following a betaine-rich diet (P=0.108). Small increases in urinary betaine excretion were observed following both treatments ( approximately 1.5% of supplement; approximately 1.3% of dietary betaine). Most was attributable to increased excretion of betaine as dimethylglycine. CONCLUSIONS: Supplemental or dietary betaine similarly increase circulating betaine concentrations and attenuate the post-methionine load rise in homocysteine concentrations.

Plasma dependent and independent accumulation of betaine in male and female rat tissues.

Tissue betaine is an intracellular osmolyte that also provides a store of labile methyl groups. Despite these important biological roles, there are few data regarding tissue betaine content. We measured the betaine concentration of plasma and various tissues (brain, heart, lungs, liver, kidney, spleen, intestine, reproductive tissues, skeletal muscle and skin) in male and female rats and assessed whether there were any gender-specific differences in betaine content or distribution and whether there was any relationship between tissue accumulation and plasma levels. Betaine was highest in the liver and kidney with values ranging from 1.6 to 9.5 mmol/l and 2.0 to 5.4 mmol/l, respectively. Plasma betaine concentrations were significantly lower than tissue levels except in the brain (? 25 % of plasma) and skeletal muscle (similar to plasma). Regression analysis of the combined male and female data revealed a significant plasma-related accumulation of betaine in the heart, skin and skeletal muscle, while the lung, liver, kidney, spleen, and intestine showed significant plasma-related and plasma-independent accumulations of betaine. The betaine content of the skin, liver and kidney was not significantly different between males and females, but in plasma and all tissues analyzed it was significantly higher in males (P<0.01).

Concomitant Staphylococcus aureus bacteriuria is associated with poor clinical outcome in adults with S. aureus bacteraemia.

A retrospective cohort study was undertaken to determine the prognostic significance of Staphylococcus aureus bacteriuria in patients presenting to our hospital with S. aureus bacteraemia between January 2000 and December 2003. A total of 378 patients had at least one positive blood culture for S. aureus, of whom 221 had urine cultured within 24h of presentation. For this group, 206 case records could be retrieved for review. Of these patients, all had meticillin-susceptible S. aureus bacteraemia and 35 (17%) had S. aureus cultured in urine. Logistic regression analysis was used to control for age, genitourinary tract status and comorbidity. Concomitant S. aureus bacteriuria persisted as a significant risk factor for ICU admission [risk ratio (RR): 2.5; 95% confidence interval (CI): 1.06-4.36; P=0.04] and in-hospital mortality (RR: 2.18; 95% CI: 1.05-3.57; P=0.04). Other findings were that cerebrovascular disease in males and increasing age in both sexes were associated with in-hospital and one-year mortality. Prospective studies are warranted exploring the link between S. aureus bacteriuria and clinical outcome in patients with S. aureus bacteraemia.

Incidence and characteristics of viral community-acquired pneumonia in adults.

BACKGROUND: In adults, viral causes of community-acquired pneumonia (CAP) are poorly characterised. The aims of this study were to characterise the viral aetiology of CAP in adults by using an extensive array of viral diagnostic tests and to compare the characteristics of viral pneumonia with those of pneumococcal pneumonia. METHODS: Adults admitted to Christchurch Hospital over a 1-year period with CAP were included in the study. Microbiological testing methods included blood and sputum cultures, urinary antigen testing for Streptococcus pneumoniae and Legionella pneumophila, antibody detection in paired sera and detection of respiratory viruses in nasopharyngeal swabs by immunofluorescence, culture and PCR. RESULTS: Of 304 patients with CAP, a viral diagnosis was made in 88 (29%), with rhinoviruses and influenza A being the most common. Two or more pathogens were detected in 49 (16%) patients, 45 of whom had mixed viral and bacterial infections. There were no reliable clinical predictors of viral pneumonia, although several variables were independently associated with some aetiologies. The presence of myalgia was associated with pneumonia caused by any respiratory virus (OR 3.62, 95% CI 1.29 to 10.12) and influenza pneumonia (OR 190.72, 95% CI 3.68 to 9891.91). Mixed rhinovirus/pneumococcal infection was associated with severe disease. CONCLUSIONS: Virus-associated CAP is common in adults. Polymicrobial infections involving bacterial and viral pathogens are frequent and may be associated with severe pneumonia.

Ethanol disinfection of plastic-adherent micro-organisms.

This study investigated the bactericidal effect of ethanol/water (70:30 vol:vol) against plastic-adherent organisms that commonly cause line infections. The experiments were performed in polycarbonate wells and all incubations were at 37 degrees C. Bacteria in broth were inoculated into wells and incubated (16, 40 and 72 h) before washing to remove non-adherent organisms and exposure to ethanol/water. Wells were then re-incubated with broth to detect surviving bacteria. All organisms incubated for 16 h were killed by 1h of exposure to 70% ethanol. After incubation for 40 h, 4h of exposure to ethanol was required to kill two strains of Candida albicans. Likewise, one of three of both Klebsiella pneumoniae and Pseudomonas aeruginosa, incubated for 72 h, showed growth after 1h of exposure to 70% ethanol but not after 4h of exposure. These results suggest that in contrast to log phase organisms, which are killed by ethanol/water solutions in seconds, plastic-adherent organisms are more resistant to the bactericidal activity of ethanol.

Lower limb cellulitis: features associated with length of hospital stay.

AIMS: This study aimed to identify features associated with length of hospital stay (LOHS), length of intravenous antibiotic therapy (LIVAT) and six-week outcomes for patients with lower limb cellulitis, and to test the Eron/Passos classification of cellulitis in the New Zealand system. METHODS: Eighty-five variables were collected prospectively from a cohort of 51 inpatients admitted to Christchurch hospital. The primary end-point for analysis was LOHS. LIVAT and six-week outcomes were secondary end-points. RESULTS: On univariate analysis use of diuretics, living alone, cellulitis acuity, a creatinine concentration of >0.1 mmol/l, poor mobility, pulse >90 bpm, age >70 years, oedema extent, chronic oedema, ulceration, neutrophil count >10x10(9)/l, erythema area >1000 cm2 and haemoglobin concentration less than normal were significantly (P= or <0.05) associated with LOHS. A stay of < or =3 days was associated with less oedema, absence of diuretic use and less acute cellulitis. A stay of >7 days was associated with use of diuretics, living alone, age >70 years, more oedema, erythema area >1000 cm2, haemoglobin less than normal, ulceration, creatinine >0.1 mmol/l and poor mobility. The presence of a discharge was associated with LIVAT. Multivariate analysis accounted for 48% of the variance in LOHS and 16% for LIVAT. Use of diuretics, neutrophil count >10x10(9)/l and oedema score were independently associated with LOHS, with oedema score associated with short stay and diuretic use with long stay. The Eron/Passos system was not helpful so a new scoring system was devised which successfully classified patients into length of stay groups. CONCLUSIONS: The clinical features analysed accounted for half of the variance in LOHS. An important reason may be physician discretion. If so, our scoring system based on these results could be used in a clinical pathway to improve patient care. This tool would need to be evaluated prospectively.

Diagnosis and management of staphylococcal infections of pacemakers and cardiac defibrillators.

Staphylococcal species, usually Staphylococcus aureus or Staphylococcus epidermidis, account for 70% to 95% of pacemaker and cardiac defibrillator infections. Infection limited to the generator pocket may cause pain, redness and swelling that is often accompanied by drainage or fistula formation. In this instance, the generator should be removed and reimplanted at another site as cure is rare with antimicrobial therapy alone. Infection of the leads usually tracks along the wire to include the endocardial surface and may involve the tricuspid valve and pocket. Clinical manifestations vary from mild chronic non-specific symptoms to septic shock with marked localizing signs. Septic embolization to the lungs is common and may cause cough, chest pain and shortness of breath that may be misdiagnosed. Blood culture and trans-oesophageal echocardiography (TOE) are the most important investigations.TOE has a sensitivity of >90%. Lead infection without vegetations may occur and these infections should be treated as for endocarditis. Antimicrobial therapy is an important part of treatment but lead infections are unlikely to cured unless the device is removed. Vancomycin is suitable as initial antimicrobial therapy as this covers both S. aureus and coagulase-negative staphylococci. Flucloxacillin, dicloxacillin or a first-generation cephalosporin are preferred if the organism is sensitive. The addition of low-dose gentamicin may improve bacterial killing. The duration of antimicrobial therapy and timing of replacement of the device have not been determined but 2 weeks treatment before removal and 2-4 weeks treatment after replacement is commonly administered.

Diagnosis and management of staphylococcal infections of vascular grafts and stents.

Staphylococcus aureus and coagulase-negative staphylococci are the commonest bacterial causes of both vascular graft and stent infections. Infection may occur either from direct implantation or haematogenous spread, and occurs in less than 1% of aortic grafts, 2% to 5% of inguinal grafts, and rarely in stents. Death or amputation is common following these infections despite aggressive treatment. Infection with S. aureus is usually more acute than with coagulase-negative staphylococci but both cause systemic symptoms. Inguinal infections usually cause localized swelling often with a sinus tract, bleeding or distal embolism. Aortic infections commonly present with abdominal discomfort retroperitoneal infection or a mass from a false aneurysm. Stent infections usually cause pain, swelling, erythema and circulation disturbances of the ipsilateral limb. The most useful investigations are blood cultures and computerized tomography or magnetic resonance imaging. These imaging techniques have a high sensitivity and specificity in advanced graft infections but these are considerably lower in low-grade infections. Persistence of perigraft fluid beyond 3 months after surgery is suspicious of infection. Aggressive antimicrobial therapy is an important part of management but surgery is usually required to cure both graft and stent infections. Where the organisms are susceptible, high-dose beta-lactam therapy (e.g. flucloxacillin, dicloxacillin or a first-generation cephalosporin) plus low-dose gentamicin are recommended initially. Some authorities add rifampicin after 3-5 days treatment, but this is controversial. Antimicrobial therapy can be stopped 4-6 weeks after surgery if arterial stump cultures are negative but should be continued long-term, and perhaps indefinitely, if they are positive.

Reduction of exit-site infections of tunnelled intravascular catheters among neutropenic patients by sustained-release chlorhexidine dressings: results from a prospective randomized controlled trial.

Exit-site and tunnel infections of tunnelled central intravascular catheters are a frequent source of morbidity among neutropenic patients and may necessitate catheter removal. They require antimicrobial therapy that increases healthcare costs and is associated with adverse drug reactions. A prospective randomized clinical trial was conducted among adult patients undergoing chemotherapy in a haematology unit. Tunnelled intravascular catheters were randomized to receive the control of a standard dressing regimen as recommended by the British Committee for Standards in Haematology, or to receive the intervention of a sustained-release chlorhexidine dressing. Follow-up data were available in 112 of 114 tunnelled intravascular catheters which were randomized. Exit-site or combined exit-site/tunnel infections occurred in 23 (43%) of 54 catheters in the control group, and five (9%) of 58 catheters in the intervention group [odds ratio (OR) for intervention group compared with control group =0.13, 95% confidence intervals (CI) 0.04-0.37, P<0.001]. More tunnelled intravascular catheters were prematurely removed from the control group than the intervention group for documented infections [20/54 (37%) vs 6/58 (10%), OR=0.20, 95%CI 0.53-0.07]. However, there was no difference in the numbers of tunnelled intravascular catheters removed for all proven and suspected intravascular catheter-related infections [21/54 (39%) vs 19/58 (33%)], or in the time to removal of catheters for any reason other than death or end of treatment for underlying disease. Thus chlorhexidine dressings reduced the incidence of exit-site/tunnel infections of indwelling tunnelled intravascular catheters without prolonging catheter survival in neutropenic patients, and could be considered as part of the routine management of indwelling tunnelled intravascular catheters among neutropenic patients.

Diagnosis of aspergillus peritonitis in a renal dialysis patient by PCR and galactomannan detection.

This report describes the use of the polymerase chain reaction (PCR) and galactomannan detection to detect aspergillus in the continuous ambulatory peritoneal dialysis (CAPD) fluid and blood of a patient with multiple myeloma on CAPD and immunosuppressive treatment. Diagnosis of aspergillosis was initially made by conventional culture of CAPD fluid, but the PCR and galactomannan assays also detected aspergillus DNA and antigen in the blood, respectively. This suggests that the PCR and galactomannan assays, previously suggested as useful in the management of invasive fungal infections in neutropenic haematological patients, may be suitable for application to a broad range of clinical situations and sample types.

Trigonelline is not responsible for the acute increase in plasma homocysteine following ingestion of instant coffee.

OBJECTIVE: To determine whether trigonelline contributes to the effect of coffee on homocysteine (Hcy). DESIGN AND INTERVENTIONS: This was a randomised crossover study. Subjects consumed 50 mg trigonelline, 5 g of instant coffee (approximately 50 mg trigonelline) or water, consumed as a single dose in 100 ml, with 1 week between each treatment. Blood samples were drawn fasting and hourly for 8 h. Urine samples were collected pretreatment and every 2 h for 8 h. SETTING: Christchurch Clinical Studies Trust, Christchurch, New Zealand. SUBJECTS: Eight healthy male subjects. RESULTS: Instant coffee raised plasma Hcy concentrations compared with water (P=0.019) and trigonelline (P=0.037). Plasma Hcy concentrations were not different between water and trigonelline treatments (P=0.789). The change in plasma Hcy concentration was higher (mean+/-s.e.) 4 h (0.7+/-0.2 micromol/l, P=0.006), 5 h (0.7+/-0.2 micromol/l, P=0.013) and 7 h (0.7+/-0.2 micromol/l, P=0.024) following coffee consumption. Urinary glycine betaine excretion was increased by coffee but not by trigonelline. CONCLUSION: Ingestion of instant coffee acutely elevated plasma Hcy; however, trigonelline is not responsible for this rise. SPONSORSHIP: Supported by the Health Research Council, the Canterbury Medical Foundation, the Foundation of Research, Science and Technology.

Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations.

BACKGROUND: Hyperhomocysteinemia is a risk factor for atherosclerosis that is common in chronic renal failure (CRF), but its cause is unknown. Homocysteine metabolism is linked to betaine-homocysteine methyl transferase (BHMT), a zinc metalloenzyme that converts glycine betaine (GB) to N,N dimethylglycine (DMG). DMG is a known feedback inhibitor of BHMT. We postulated that DMG might accumulate in CRF and contribute to hyperhomocysteinemia by inhibiting BHMT activity. METHODS: Plasma and urine concentrations of GB and DMG were measured in 33 dialysis patients (15 continuous ambulatory peritoneal dialysis and 18 hemodialysis), 33 patients with CRF, and 33 age-matched controls. Concentrations of fasting plasma total homocysteine (tHcy), red cell and serum folate, vitamins B(6) and B(12), serum zinc, and routine biochemistry were also measured. Groups were compared, and determinants of plasma tHcy were identified by correlations and stepwise linear regression. RESULTS: Plasma DMG increased as renal function declined and was twofold to threefold elevated in dialysis patients. Plasma GB did not differ between groups. The fractional excretion of GB (FE(GB)) was increased tenfold, and FED(MG) was doubled in CRF patients compared with controls. Plasma tHcy correlated positively with plasma DMG, the plasma DMG:GB ratio, plasma creatinine, and FE(GB) and negatively with serum folate, zinc, and plasma GB. In the multiple regression model, only plasma creatinine, plasma DMG, or the DMG:GB ratio was independent predictors of tHcy. CONCLUSIONS: DMG accumulates in CRF and independently predicts plasma tHcy concentrations. These findings suggest that reduced BHMT activity is important in the pathogenesis of hyperhomocysteinemia in CRF.