Ambient and at-the-ear occupational noise exposure and serum lipid levels.

OBJECTIVES: Occupational and residential noise exposure has been related to increased risk of cardiovascular disease. Alteration of serum lipid levels has been proposed as a possible causal pathway. The objective of this study was to investigate the relation between ambient and at-the-ear occupational noise exposure and serum levels of total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and triglycerides when accounting for well-established predictors of lipid levels. METHODS: This cross-sectional study included 424 industrial workers and 84 financial workers to obtain contrast in noise exposure levels. They provided a serum sample and wore portable dosimeters that every 5-s recorded ambient noise exposure levels during a 24-h period. We extracted measurements obtained during work and calculated the full-shift mean ambient noise level. For 331 workers who kept a diary on the use of a hearing protection device (HPD), we subtracted 10 dB from every noise recording obtained during HPD use and estimated the mean full-shift noise exposure level at the ear. RESULTS: Mean ambient noise level was 79.9 dB (A) [range 55.0-98.9] and the mean estimated level at the ear 77.8 dB (A) [range 55.0-94.2]. Ambient and at-the-ear noise levels were strongly associated with increasing levels of triglycerides, cholesterol-HDL ratio, and decreasing levels of HDL-cholesterol, but only in unadjusted analyses that did not account for HPD use and other risk factors. CONCLUSION: No associations between ambient or at-the-ear occupational noise exposure and serum lipid levels were observed. This indicates that a causal pathway between occupational and residential noise exposure and cardiovascular disease does not include alteration of lipid levels.

Skeletal muscle adaptation to immobilization and subsequent retraining in elderly men: No effect of anti-inflammatory medication.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) may enhance resistance training induced gain in skeletal muscle mass and strength, but it is unknown if NSAIDs affects muscle loss during periods of inactivity in elderly individuals. Thus, we studied the influence of NSAID treatment on human skeletal muscle during immobilization and rehabilitation resistance training (retraining). METHODS: 19 men (60-80yrs, range) were randomly assigned to ibuprofen (1200mg/d, Ibu) or placebo (Plc). One lower limb was immobilized in a cast for 2weeks and retrained for 6weeks. Moreover, whey protein isolate was ingested (2×20g/d) throughout the whole study period. Plasma inflammatory markers, quadriceps muscle mass and strength, and muscle gene expression were investigated. RESULTS: Muscle mass and strength decreased after 2weeks of immobilization (P<0.001), but returned to baseline levels after 2weeks of retraining combined with whey protein supplementation (P<0.001). Furthermore, muscle mass and strength reached beyond baseline levels after 6weeks of retraining (p<0.05), and NSAID did not significantly affect this (p>0.05). No group-differences, but differences over time, were observed for muscle gene expression of proteolytic and anabolic factors. Plasma inflammatory markers were unaffected by the study intervention and NSAID treatment. CONCLUSION: Two weeks of lower limb immobilization lead to a reduction in muscle mass and strength, but these parameters were restored already after2 weeks of retraining and whey protein supplementation. After 6weeks of retraining and whey protein supplementation, muscle mass and strength increased beyond baseline levels, and NSAID treatment did not significantly influence this in elderly.

Non-antibiotics reverse resistance of bacteria to antibiotics.

BACKGROUND: Most clinical isolates that exhibit a multi-drug resistant phenotype owe that resistance to over-expressed efflux pumps. Compounds that are efflux pump inhibitors (EPIs) reduce or reverse resistance to antibiotics to which the bacterial strain is initially resistant. We have evaluated non-antibiotics to reduce resistance of commonly encountered bacterial pathogens to antibiotics. MATERIALS AND METHODS: The effect of non-antibiotics on the susceptibility of bacteria to antibiotics was conducted by minimum inhibition concentration determinations of the antibiotic in the absence and presence of the non-antibiotic. RESULTS: Non-antibiotics such as chlorpromazine, amitryptiline and trans-chlorprothixene are shown to reduce or reverse resistance of a variety of bacteria to antibiotics. CONCLUSION: The results suggest that non-antibiotics may serve as adjuncts to conventional antibiotics for the therapy of problematic antibiotic infections caused by bacteria that owe their resistance to over-expressed efflux pumps.

Availability and comparability of human biomonitoring data across Europe: a case-study on blood-lead levels.

Recently, it has become clear that the complexity of environmental health issues requires an approach that takes into account the complexities, interdependencies and uncertainties of the real world. An urgent issue that has surfaced is the need for accurate tools to better describe exposure characterization to environmental chemicals. By including human biomonitoring (HBM) data, a greater precision in exposure and associated risk estimates and more accurate dose-response relationships may be achieved. A restricting issue still is the availability of reliable and comparable HBM data. The aim of the current study was twofold: (1) to find out whether it is practically feasible to collect raw, individual HBM data across Europe; and (2) to evaluate the comparability and use of these HBM data for environmental health impact assessment at a European scale. Blood-lead (B-Pb) was selected as the chemical of choice because of its long history as an environmental pollutant in HBM programs and its known public health relevance. Through literature search and identification of HBM experts across Europe, HBM programs that measured B-Pb were identified and asked to share individual data on age, gender and B-Pb levels. Following this request, more than 20,000 individual data points from 8 European countries were collected. Analysing these data made clear that it is difficult to use disparate data collections because of the inherent variability with respect to the gender and age of participants and calendar-years sampled. When these confounders were taken however, there was no additional variability in B-Pb distributions among different countries. It was concluded that while it is possible to collect HBM data from different sources across Europe, the need to get data from comparable (sub-)populations is essential for appropriate use and interpretation of HBM data for environmental health impact assessment.

Responses of algesic and metabolic substances to 8 h of repetitive manual work in myalgic human trapezius muscle.

The trapezius muscle often develops pain as the result of repetitive and stressful work tasks although it is unclear to what extent this pain is due to alterations in muscle concentrations of algesic/nociceptive substances. Twenty women with chronic neck- and shoulder pain (TM) whose work required highly repetitive work tasks and 20 pain-free female colleagues (CON) were studied during and after a full 8-hour workday. We collected microdialysates from their dominant/most painful trapezius muscle; concentrations of serotonin, glutamate, lactate, pyruvate, potassium, bradykinin, and cytokines and blood flow were determined. In addition, we measured surface electromyogram, task exposure level, pain intensity, perceived mental stress, and urine-cortisol. In connection to the clinical neck and shoulder examination, we determined pressure pain thresholds (PPTs) over the trapezius and tibialis muscles. TM had higher concentrations of glutamate (71+/-42 vs. 36+/-15 micromol l(-1)) and pyruvate (187+/-89 vs. 125+/-63 micromol l(-1)) than CON. Interstitial serotonin was higher in TM (before work: 10.6+/-10.8 vs. 2.2+/-1.2 nM; after work: 9.2+/-8.3 vs. 1.5+/-2.9 nM). The trapezius blood flow during the working day was higher in TM than in CON. TM had lower PPT and higher pain intensity throughout the working day. No differences in EMG, task exposure level, mental stress, or urine-cortisol in the groups were found. These findings support the idea that peripheral nociceptive processes are activated in occupationally active subjects, who are diagnosed with trapezius myalgia. In contrast, no sign of low blood flow or increased stress or muscle activity markers were found in TM.

New methods for the identification of efflux mediated MDR bacteria, genetic assessment of regulators and efflux pump constituents, characterization of efflux systems and screening for inhibitors of efflux pumps.

We have developed a number of methods that identify efflux pump mediated multi-drug resistant bacteria, characterize efflux systems and screen for inhibitors of efflux pumps. These approaches were complemented by the quantification of the expression of genes that regulate and code for constituents of efflux pumps. The methods described are easy to use, reproducible and for the most part, require instrumentation normally present in a clinical bacteriology laboratory. Because each method provides good reproducibility, they lend themselves for inter-laboratory use.

Promising therapy of XDR-TB/MDR-TB with thioridazine an inhibitor of bacterial efflux pumps.

Global rates of pulmonary tuberculosis (TB) continue to increase. Moreover, resistance of the causative organism Mycobacterium tuberculosis to the two most effective anti-TB medications continue to rise. Now, multi-drug resistant TB (MDR-TB) has progressed to extensively drug resistant TB (XDR-TB) - a M. tuberculosis organism that is resistant to the most effective second line drugs available for the treatment of TB. This review provides detailed, significant evidence that supports the use of an old neuroleptic compound, thioridazine (TZ), for the management of MDR-TB and XDR-TB infections and which has been shown to inhibit efflux pumps of bacteria. The argument has been previously presented but no one seems to be listening - and the disease continues unabated when there is a very good probability that the suggested drug will prove to be effective. When the prognosis is poor, available therapy predictably ineffective and death is inevitable, compassionate therapy with TZ should be contemplated. The risks are small and the rewards great.

Flucloxacillin associated neutropenia in children treated for bone and joint infections.

OBJECTIVE: This report describes episodes of acute neutropenia associated with flucloxacillin use in children treated for bone and joint infections. METHODS: A retrospective chart audit was performed on eight children who developed neutropenia when treated with flucloxacillin. RESULTS: Eight children (aged 1 month to 13 years) had a diagnosis of neutropenia attributed to treatment with flucloxacillin, seven of whom received parenteral therapy. The time to onset of neutropenia averaged 27 days, with neutrophil counts returning to normal limits in all patients after 2 to 9 days. Two children were asymptomatic when the neutropenia was detected. The average flucloxacillin dose used was 65% (range 20-100%) of the recommended maximum dose. CONCLUSIONS: These cases suggest that flucloxacillin should be used with greater caution and guidelines for dosing and clinical monitoring (regular neutrophil counts) need to be reassessed, despite none of these patients experiencing serious sequelae.

Interstitial muscle lactate, pyruvate and potassium dynamics in the trapezius muscle during repetitive low-force arm movements, measured with microdialysis.

AIM: Local muscle metabolic responses to repetitive low-force contractions and to intense static contractions were studied by microdialysis in humans. METHODS: Microdialysate and electromyography (EMG) were sampled from the trapezius muscle, mixed venous blood samples were taken and perceived exertion was rated (0-9) before and during 20 min of standardized repetitive arm movement (REP), 60 min recovery (R1), and 10 min 90 degrees sustained arm position (SUS) at 20% maximum voluntary contraction, followed by 60 min recovery (R2) in six healthy male participants (28-33 years). RESULTS: Average muscle activity was 8 +/- 2% of EMGmax-RMS (mean +/-SEM) during REP and 22 +/- 5% of EMGmax-RMS during SUS. Perceived exertion increased from 0 to 3.2 +/- 0.5 during REP and from 0 to 8.5 +/- 0.3 during SUS. During REP interstitial muscle lactate increased from 2.1 +/- 0.2 to 2.9 +/- 0.2 mmol L(-1) (P < 0.001) and returned to the baseline level during R1, while dialysate [K+] increased from 3.8 +/- 0.2 to 4.7 +/- 0.2 mmol L(-1) (P < 0.002) and returned to 3.8 +/- 0.2 mmol L(-1) during R1. In contrast, plasma lactate and [K+] remained unchanged. During SUS interstitial muscle lactate increased from 2.3 +/- 0.2 to 3.3 +/- 0.3 mmol L(-1) (P < 0.003), increased further to 6.5 +/- 1.3 mmol L(-1) post-exercise (P < 0.001) and returned to baseline levels during R2. Dialysate [K+] increased from 3.9 +/- 0.2 to 4.6 +/- 0.2 mmol L(-1) (P < 0.05) and returned to baseline level during R2. Plasma lactate increased significantly during SUS whereas plasma [K+] was unchanged. During REP and SUS interstitial pyruvate was unchanged but increased in the post-exercise period proportional to the exercise intensity. CONCLUSIONS: The microdialysis technique was effective in revealing muscle metabolic events that were not found systemically. Furthermore, the trapezius muscle showed an anaerobic metabolism during low-force contraction, which could indicate inhomogeneous muscle activation.

The in-vitro antimicrobial effect of non-antibiotics and putative inhibitors of efflux pumps on Pseudomonas aeruginosa and Staphylococcus aureus.

The anti-microbial activity of six non-antibiotics (one amino-ethylchloride, three phenothiazines, two tricyclic antidepressives) were tested on 20 clinical isolates of Pseudomonas aeruginosa, one clinical isolate of Klebsiella pneumoniae, 2 ATTC strains and 14 clinical isolates of Staphylococccus aureus, using the plate dilution method. The effects on P. aeruginosa were independent of antibiotic resistance pattern and the species Stenotrophomonas maltophilia was found to be the most susceptible to the non-antibiotics, with MIC values as low as 20 mg/l for some of the substances. The 16 S. aureus strains tested were all particularly susceptible to the anti-microbial effects of the putative inhibitors of efflux pumps thioridazine and trifluoperazine with MIC values of < or =16 mg/l independently of the methicillin resistance profile of the strains. Because phenothiazines are well known to inhibit efflux pumps our results may indicate the existence of such pumps. Current works in progress are attempts at reversing the antibiotic resistance of selected bacterial strains using specific non-antibiotics and their stereo-chemical isomers.

Performance of PCR-restriction fragment length polymorphism analysis of the Helicobacter pylori ureB gene in differentiating gene variants.

Recently, PCR-restriction fragment length polymorphism (PCR-RFLP) of the urease genes of Helicobacter pylori was evaluated in a meta-analysis; acceptable discriminatory indices of the ureAB and C genes were found. In the present investigation, we found a discriminatory index of 0.95 for 191 unrelated clinical H. pylori isolates with PCR-RFLP typing of the ureB gene (933 bp), combining the results obtained with restriction enzymes HaeIII and Sau3A, and a mixture of the enzymes. We therefore find that PCR-RFLP typing of the ureB gene of H. pylori with restriction enzymes HaeIII and Sau3A is comparable to typing of other H. pylori urease genes.

Evaluation, including effects of storage and repeated freezing and thawing, of a method for measurement of urinary creatinine.

The aims of this study were to elucidate to what extent storage and repeated freezing and thawing influenced the concentration of creatinine in urine samples and to evaluate the method for determination of creatinine in urine. The creatinine method was based on the well-known Jaffe's reaction and measured on a COBAS Mira autoanalyser from Roche. The main findings were that samples for analysis of creatinine should be kept at a temperature of -20 degrees C or lower and frozen and thawed only once. The limit of detection, determined as 3 x SD of 20 determinations of a sample at a low concentration (6.1 mmol/L), was 0.3 mmol/L, and the recovery of a certified reference material was 97%. The relative precision at 3.15 mmol/L was 2.3%. It was concluded that the method is appropriate for measurement of urinary creatinine.

Phenothiazines: potential alternatives for the management of antibiotic resistant infections of tuberculosis and malaria in developing countries.

The in vitro and in vivo activity of phenothiazines against antibiotic susceptible and antibiotic resistant Mycobacterium tuberculosis and malaria-causing Plasmodia is reviewed. Given the facts that pulmonary tuberculosis and malaria are the major causes of death in developing countries, that both of these infections continue to escalate in their resistance to antibiotics, that the cost for the management of these infections is beyond that afforded by most developing nations, and lastly, that new and effective agents are not forthcoming from the pharmaceutical industry, the scientific rationale for the potential use of select phenothiazines for the management of these infections is presented.

Phenothiazines: potential management of Creutzfeldt-Jacob disease and its variants.

Creutzfeldt-Jakob disease acquired from bovines (nvCJD) has been responsible for nearly 100 deaths in the UK and thousands more may die in the years to come. New variant CJD (nvCJD) is incurable and although clinical diagnosis is becoming more precise, the diagnosis is only certain at autopsy. Phenothiazine derivatives inhibit production of prions, the disease causing agent, in cultured neuroblastoma cells, and an advanced case of nvCJD was recently brought to remission by the use of these agents in combination with an antimalarial. In this review we present direct and circumstantial evidence in support of a model describing the manner by which the intracellular antimicrobial activity of phenothiazines might cause the destruction of intracellular prions.

Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: a review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy.

The in vitro and in vivo anti-mycobacterial activities of a number of phenothiazine compounds are reviewed. These compounds, normally employed for the management of psychosis, inhibit the growth in vitro of Mycobacterium tuberculosis at concentrations that are significantly greater than those that can safely be achieved in a patient harbouring these infections. Nevertheless, one of these phenothiazines, chlorpromazine, is concentrated by human macrophages to 10-100 times its concentration in plasma, and has activity against mycobacteria that have been phagocytosed by these cells. Phenothiazines have significant in vitro activity against susceptible, polydrug- and multidrug-resistant strains of M. tuberculosis, as well as enhancing the activity of some agents employed for first-line treatment. Because thioridazine, the very mild anti-psychotic agent whose most common side effect is drowsiness, has equal anti-tuberculosis properties in vitro to chlorpromazine, we recommend that thioridazine be studied as an adjuvant to the four- or five-drug regimens employed for the management of a freshly diagnosed tuberculosis infection of unknown antibiotic susceptibility, at least during the period required for the assessment of antibiotic susceptibility. Because it also enhances the activity of rifampicin and streptomycin, antibiotics that frequently have adverse effects, additional studies evaluating the use of thioridazine as an adjuvant may eventually allow a reduction in the dosages of these antibiotics and result in a decreased frequency of adverse effects. It is important to note that whereas the management of patients with thioridazine for periods in excess of many months will result in the appearance of some undesirable side effects, its use for a limited period of 2-3 months should not produce side effects that are more severe than simple drowsiness. Nevertheless, further in vitro and in vivo studies are essential before thioridazine may be recommended for the management of select cases of pulmonary tuberculosis.

Description of a generally applicable model for the evaluation of uncertainty of measurement in clinical chemistry.

There is a growing pressure on clinical chemistry laboratories to conform to quality standards that require the evaluation and expression of the uncertainty of results of measurement. Nevertheless, there is some reluctance to accept the uncertainty concept in the analytical community due to difficulty in evaluating uncertainty in practice. For example, often the uncertainty of some uncertainty components is not known very well in clinical chemistry measurements, such as those associated with matrix effects or with the values of the calibrators. Moreover, it is not clear how to interpret uncertainty in relation to diagnostic criteria, reference ranges and other decision limits in clinical chemistry practice. Hence, the value of reporting the uncertainty of the measurement result is not obvious. In this paper it is suggested a relatively simple, logical procedure for evaluating measurement uncertainty based on the principles in the Guide for the Expression of Uncertainty of Measurement (GUM). The measurement process is partitioned into elements that are well known to the analyst, namely sampling, calibration, and analysis. The corresponding model function expresses the result of a measurement as the value obtained by the analytical procedure multiplied by the correction factors for sampling bias, for bias caused by the calibrators, and for other types of bias. Under normal conditions, when the measurement procedure is validated and corrected for all known bias, the expected value of each correction factor is one. The uncertainty that remains with regard to sampling, manufacturing of calibrators and other types of bias is combined with the analytical imprecision to yield a combined uncertainty of a result of measurement. The advantages of this approach are: (i) Data from the method validation, internal quality control and from participation in external quality control schemes can be used as input in the uncertainty evaluation process. (ii) The partition of the measurement into well-defined tasks highlights the different responsibilities of the clinical chemistry laboratory and of the manufacturer of reagents and calibrators. (iii) The approach can be used to harmonize the uncertainty evaluation process, which is particularly relevant for laboratories seeking accreditation under ISO 17025. The application of the proposed model is demonstrated by evaluating the uncertainty of a result of a measurement of prolactin in human serum. In the example it is shown how to treat the uncertainty associated with a calibrator supplied with a commercial analytical kit, and how to evaluate the uncertainty associated with matrix effects.

Repeated exposures to cobalt or chromate on the hands of patients with hand eczema and contact allergy to that metal.

The present study aimed at evaluating the effects of daily repeated exposures to low cobalt or chromate concentrations on the hands of patients with hand eczema and cobalt or chromate allergy. For 2 weeks, the patients immersed a finger for 10 min daily into the appropriate metal salt solution in water. During the 1st week, this was a 10 or 50 mg/l cobalt concentration or a 10 mg/l chromate concentration, and, during the 2nd week, a 100 or 200 mg/l cobalt concentration or a 100 mg/l chromate concentration. This regimen elicited a flare of hand eczema only in the chromate-exposed chromate-sensitive patients. During the exposure period, accumulation of cobalt or chromate in the nail was demonstrated. Standardization of chemical methods of quantification of skin exposure to allergens, combined with experimental exposure studies in patients with specific contact allergy, will increase the possibility of providing evidence-based medicine in the area of allergic contact dermatitis in the future.

Nickel-induced cytokine production from mononuclear cells in nickel-sensitive individuals and controls. Cytokine profiles in nickel-sensitive individuals with nickel allergy-related hand eczema before and after nickel challenge.

Exposure to nickel is a major cause of allergic contact dermatitis which is considered to be an inflammatory response induced by antigen-specific T cells. Here we describe the in vitro analysis of the nickel-specific T-cell-derived cytokine response of peripheral blood mononuclear cells from 35 nickel-allergic and 30 non-nickel-allergic individuals. Peripheral blood mononuclear cells were stimulated with 10(-4) and 10(-5) mol/l NiSO4 for 6 days and then additionally with ionomycin and phorbol myristate acetate for 24 h. Culture supernatants were analysed for interleukin-4 (IL-4), IL-5, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) by quantitative ELISA. The analysis showed that the synthesis of IL-4 and IL-5 but not of IFN-gamma or TNF-alpha was significantly higher in the nickel-allergic individuals. The finding of preferential synthesis of Th2 cytokines was somewhat of a surprise, since previous studies have suggested a Th1 response in nickel-mediated allergic contact dermatitis. Subsequently, the nickel-allergic individuals were randomized to experimental exposure to nickel or vehicle in a double-blind design. A daily 10-min exposure of one finger to 10 ppm nickel solution for 1 week followed by 100 ppm for an additional week evoked a clinical response of hand eczema in the nickel-exposed group. Blood samples were drawn on days 7 and 14 after the start of this exposure to occupationally relevant concentrations of nickel. No statistically significant differences were observed in the nickel-induced in vitro cytokine response during the exposure period. Our results indicate the possibility that IL-4 and IL-5 are involved in the pathogenesis of nickel-mediated contact dermatitis.

Phenothiazines: an alternative to conventional therapy for the initial management of suspected multidrug resistant tuberculosis. A call for studies.

Increased frequency of multidrug resistant strains of Mycobacterium tuberculosis results from inappropriate treatment and lack of patient compliance. The Center for Disease Control/American Thoracic Society (CDC/ATS) guidelines issued for the management of newly diagnosed cases of tuberculosis (TB) will not be totally effective regardless of adherence to the guidelines and patient cooperation. The long interim period between the diagnosis of TB and confirmation of antibiotic susceptibility contributes to the infection rate. Consequently, the use of an adjuvant that is known to inhibit all encountered multidrug resistant strains of M. tuberculosis may be helpful until antibiotic susceptibility is known. Phenothiazines such as chlorpromazine, methdilazine and thioridazine are effective against strains of M. tuberculosis in vitro and in vivo. It is recommended that studies be designed and conducted for the purpose of managing new cases of TB that emanate from areas known to harbour multidrug resistant strains of M. tuberculosis, with phenothiazines as adjuvants to the regimen recommended by the CDC/ATS guidelines until antibiotic susceptibility is defined. Because the normal maximum period for obtaining conventional antibiotic susceptibility results is less than 7 or 8 weeks, the probability of serious side effects from the use of a phenothiazine is remote.

Inhibition of HIV replication by neuroleptic agents and their potential use in HIV infected patients with AIDS related dementia.

A series of neuroleptic agents and their structural isomers have been tested as inhibitors of HIV-replication. At non-toxic concentrations, cis (Z)- and trans (E)-flupentixol and several derivatives of the 5HT-uptake-inhibitors paroxetine and femoxetine, inhibit HIV-1 replication. The findings indicated that these compounds could be used in combination with other anti-retroviral therapy in HIV-1 infected patients with AIDS-related dementia.