Differences in WHOQOL-100 domain scores in Parkinson's disease and osteoarthritis

BACKGROUND: The aim was to compare health-related quality of life (QOL) in patients with Parkinson's disease, osteoarthritis, and persons of a matched control group. MATERIAL/METHODS: The study was done in 178 patients (94 men and 84 women, 54 with Parkinson's disease and 58 with osteoarthritis) and 66 age- and sex-matched controls. The patients were randomly selected from a register of community health maintenance organizations. The main outcome measures were WHOQOL-100 domains and overall QOL. RESULTS: The mean scores of most of the WHOQOL-100 domains were significantly poorer for the Parkinson's disease patients. As expected, the scores for "mobility", "activities in daily living", and "working capacity" of the level-of-independence domain were significantly poorer in this group than in the osteoarthritis and control groups. These results indicate that the generic WHOQOL questionnaire discriminated between PD and OA patients, was sensitive to some aspects of patients' QOL perception and multidimensional problems, and was able to differentiate between PD and OA patients in the level-of-independence domain and in the facets we might expect to be mostly affected by the diseases. The frequencies of the separate clinical forms of Parkinson's disease were: rigidity-tremor in 76.8% of patients, rigidity in 13.7%, and tremor in 9.5%. CONCLUSIONS: The patient groups showed the most changes in WHOQOL-100 domains with respect to all facets of the level-of-independence domain, "energy and fatigue" of the physical domain, and three facets of the environment domain. Impairment of QOL included more aspects of QOL in Parkinson's disease than in osteoarthritis patients.     

Efficacy, safety, and plasma pharmacokinetics of escalating dosages of intravenously administered ravuconazole lysine phosphoester for treatment of experimental pulmonary aspergillosis in persistently neutropenic rabbits

Ravuconazole is a new antifungal triazole with broad-spectrum activity and a long half-life in plasma. We studied the antifungal efficacy, safety, and pharmacokinetics of ravuconazole lysine phosphoester in escalating dosages for the treatment of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment groups consisted of rabbits treated with ravuconazole at 2.5 (RVC2.5), 5 (RVC5), and 10 (RVC10) mg/kg of body weight/day, rabbits treated with amphotericin B (AMB) at 1 mg/kg/day, or untreated controls. There was a dose-dependent reduction of pulmonary residual fungal burden (CFU per gram) in RVC5-, RVC10-, and AMB-treated rabbits in comparison to untreated controls (P < 0.01, P < 0.001, and P < 0.01, respectively). These findings correlated with progressive galactomannan antigenemia in untreated controls and the RVC2.5-treated rabbits, a lower galactomannan index (GMI) in RVC5- and RVC10-treated rabbits, and a similarly low GMI in AMB-treated rabbits (P < 0.01). Rabbits treated with RVC5, RVC10, and AMB also showed a reduction of organism-mediated pulmonary injury, as measured by infarct scores and lung weights, in comparison to untreated controls (P < 0.001). These results were supported by decreased pulmonary infiltrates detected by computed tomography in RVC5- and RVC10-treated rabbits in comparison to untreated controls (P < 0.05). Survival throughout the entire study was achieved in 95% of RVC5-treated rabbits (P < 0.001), 85% of RVC10-treated rabbits (P < 0.001), and 50% of AMB-treated rabbits (P < 0.05) in comparison to none of the untreated controls. Ravuconazole showed linear plasma pharmacokinetics and a large volume of distribution while maintaining concentrations in plasma above the MIC throughout the dosing interval. There was no evidence of hepatotoxicity or nephrotoxicity among ravuconazole-treated animals. Intravenously administered ravuconazole lysine phosphoester showed dose-dependent efficacy and an excellent safety profile for the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits.     

Antifungal activity and pharmacokinetics of posaconazole (SCH 56592) in treatment and prevention of experimental invasive pulmonary aspergillosis: correlation with galactomannan antigenemia

The antifungal efficacy, safety, and pharmacokinetics of posaconazole (SCH 56592) (POC) were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal therapy consisted of POC at 2, 6, and 20 mg/kg of body weight per os; itraconazole (ITC) at 2, 6, and 20 mg/kg per os; or amphotericin B (AMB) at 1 mg/kg intravenously. Rabbits treated with POC showed a significant improvement in survival and significant reductions in pulmonary infarct scores, total lung weights, numbers of pulmonary CFU per gram, numbers of computerized-tomography-monitored pulmonary lesions, and levels of galactomannan antigenemia. AMB and POC had comparable therapeutic efficacies by all parameters. By comparison, animals treated with ITC had no significant changes in outcome variables in comparison to those of untreated controls (UC). Rabbits receiving prophylactic POC at all dosages showed a significant reduction in infarct scores, total lung weights, and organism clearance from lung tissue in comparison to results for UC (P < 0.01). There was dosage-dependent microbiological clearance of A. fumigatus from lung tissue in response to POC. Serum creatinine levels were greater (P < 0.01) in AMB-treated animals than in UC and POC- or ITC-treated rabbits. There was no elevation of serum hepatic transaminase levels in POC- or ITC-treated rabbits. The pharmacokinetics of POC and ITC in plasma demonstrated dose dependency after multiple dosing. The 2-, 6-, and 20-mg/kg dosages of POC maintained plasma drug levels above the MICs for the entire 24-h dosing interval. In summary, POC at > or =6 mg/kg/day per os generated sustained concentrations in plasma of > or =1 microg/ml that were as effective in the treatment and prevention of invasive pulmonary aspergillosis as AMB at 1 mg/kg/day and more effective than cyclodextrin ITC at > or =6 mg/kg/day per os in persistently neutropenic rabbits.     

Compartmental pharmacokinetics of the antifungal echinocandin caspofungin (MK-0991) in rabbits

The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (C(max)) +/- standard error of the mean increased from 16.01 +/- 0.61 microg/ml at the 1-mg/kg dose to 105.52 +/- 8.92 microg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 +/- 2.37 to 158.43 +/- 15.58 microg. h/ml, respectively. The mean apparent volume of distribution at steady state (Vd(ss)) was 0.299 +/- 0.011 liter/kg at the 1-mg/kg dose and 0.351 +/- 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 +/- 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 +/- 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increased Vd(ss), there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi.     

Antifungal Efficacy,Safety, and Single-Dose Pharmacokinetics of LY303366, a Novel Echinocandin B,in Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits

{"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366 is a novel semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1,3)-β-d-glucan synthase. The antifungal efficacy and safety of {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of body weight per day or with {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366 at 1, 5, 10, and 20 mg/kg/day. In rabbits treated with {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured by the number of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. Rabbits receiving prophylactic {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366 had comparable therapeutic efficacies by all parameters with the exception of reduction in tissue burden of A. fumigatus, where AmB was superior to {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366. {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels above the MIC for 18 h, and dosages of ≥5 mg/kg maintained plasma drug levels above the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366-treated rabbits. In summary, {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic rabbits.The echinocandins are a new class of semisynthetic lipopeptide antifungal compounds, with potent and relatively broad-spectrum antifungal activity. They act by inhibiting the synthesis of (1,3)-β-d-glucan, an integral component of the fungal cell wall, resulting in cell wall damage and ultimately cell death (13, 15). The novel mode of action and potent antifungal activity in vitro have led to the design of several new compounds for potential clinical development.Cilofungin was the first echinocandin B derivative developed for clinical trials. This compound had excellent in vitro activity against Candida spp. and was highly effective in animal models of disseminated candidiasis (12–15, 28). The compound also showed activity in a murine model of disseminated aspergillosis (6, 29). However, clinical development of cilofungin was discontinued when toxicity due to the vehicle was observed.In recent years, a new generation of echinocandins has emerged. {"type":"entrez-nucleotide","attrs":{"text":"LY303366","term_id":"1257625064"}}LY303366 (LY), a terphenyl-substituted echinocandin B, is the lead compound of this class for clinical investigation (4, 5, 10). Current in vitro studies demonstrate potent and non-cross-resistant antifungal activity against Candida albicans, Candida tropicalis, Candida glabrata, and other Candida species (7, 22, 30). The drug has also been shown to be active against Aspergillus spp. in vitro (20). Little is known, however, about the in vivo efficacy of LY against Aspergillus infections. Zeckner et al. (29) demonstrated improved survival and decreased tissue burden of Aspergillus fumigatus.Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in patients with persistent neutropenia (18, 24). The in vitro activity and preliminary in vivo antifungal effects in nonneutropenic mice suggest that LY may be an effective agent against this disease (16, 23, 29). Therefore, we investigated the antifungal efficacy and safety of LY in treatment and prophylaxis of primary pulmonary aspergillosis in persistently neutropenic rabbits.     

Safety and Efficacy of Multilamellar Liposomal Nystatin against Disseminated Candidiasis in Persistently Neutropenic Rabbits

The activity of liposomal nystatin (L-Nys) against subacute disseminated candidiasis was investigated in persistently neutropenic rabbits. Antifungal therapy was administered for 10 days starting 24 h after intravenous inoculation of 10(3) blastoconidia of Candida albicans. Responses to treatment were assessed by the quantitative clearance of the organism from blood and tissues. Treatments consisted of L-Nys at dosages of 2 and 4 mg/kg of body weight/day (L-Nys2 and L-Nys4, respectively) amphotericin B deoxycholate at 1 mg/kg/day (D-AmB), and fluconazole at 10 mg/kg/day (Flu). All treatments were given intravenously once daily. Compared to the results for untreated but infected control animals, treatment with L-Nys2, L-Nys4, D-AmB, and Flu resulted in a significant clearance of the residual burden of C. albicans from the kidney, liver, spleen, lung, and brain (P < 0.0001 by analysis of variance). When the proportion of animals infected at at least one of the five tissue sites studied was evaluated, a dose-dependent response to treatment with L-Nys was found (P < 0.05). Compared to D-AmB-treated rabbits, mean serum creatinine and blood urea nitrogen levels at the end of therapy were significantly lower in animals treated with L-Nys2 (P < 0.001) and L-Nys4 (P < 0.001 and P < 0.01, respectively). L-Nys was less nephrotoxic than conventional amphotericin B and had dose-dependent activity comparable to that of amphotericin B for the early treatment of subacute disseminated candidiasis in persistently neutropenic rabbits.     

Environmental Monitoring for Aspergillus fumigatus in Association with an Immunosuppressed Rabbit Model of Pulmonary Aspergillosis

Aspergillus fumigatus causes life-threatening pneumonia in immunocompromised patients. Conidia, the infectious form of the organism, are handled in a biologic safety cabinet under BSL2 conditions. However because germinated conidia form noninfectious hyphae in tissue, we hypothesized that rabbits inoculated intratracheally would grow A. fumigatus in their lungs but that the environment would remain free of this fungus, potentially permitting maintenance of infected animals under ABSL1 conditions. We performed a surveillance study for the presence of A. fumigatus in the environment before proceeding with antifungal therapy studies of experimental pulmonary aspergillosis. The expected outcome included absence of A. fumigatus in the environment, stool, and blood and presence in rabbit lungs. Female SPF New Zealand white rabbits were immunosuppressed and inoculated intratracheally (n = 4) or intraesophageally (n = 2) with 1.25 × 10⁸ conidia of A. fumigatus. Feces, pan liners, and walls were sampled daily during the 11-d experiment, and blood was sampled on days 2, 6, and 8 after inoculation. Samples were cultured on 5% Sabouraud glucose agar plates. Lungs were weighed and scored for hemorrhagic infarcts and homogenized for culture on 5% Sabouraud glucose agar and trypticase soy agar plates. Blood cultures, rabbit stool, and environmental swabs were all negative for A. fumigatus whereas the lungs inoculated intratracheally demonstrated 4.5 × 10² ± 0.8 × 10² CFU/g of A. fumigatus. Therefore, neutropenic rabbits with experimental invasive pulmonary aspergillosis do not shed conidia of A. fumigatus and can be safely housed under ABSL1 conditions after inoculation.Abbreviation: SGA, 5% Sabouraud glucose agarAspergillus fumigatus is an opportunistic fungal pathogen that can cause life-threatening invasive pulmonary aspergillosis, the features of which include filamentous growth within the parenchyma of the lung, intravascular thrombosis, angioinvasion, tissue infarction, and occasionally hematogenous dissemination (Figure 1).² Invasive pulmonary aspergillosis is of particular concern for severely immunocompromised patients, such as cancer patients receiving cytotoxic chemotherapy, recipients of hematopoietic stem cells or solid-organ transplants, and patients with chronic granulomatous disease.^1,4,24 Despite advances in treatment with antifungal agents, mortality rates with this infection remain high (greater than 50%), and those patients with severe immunosuppression are at highest risk.¹⁵Open in a separate windowFigure 1.Invasive pulmonary aspergillosis in a neutropenic rabbit lung. A, alveoli; BV, blood vessel wall; arrow, invasion of blood vessels by Aspergillus hyphae; *, intravascular thrombosis. Hematoxylin and eosin stain; bar, 100 µm.A. fumigatus is ubiquitous in the soil, where it thrives on organic debris. It is a widely distributed organism that sporulates abundantly, with each conidial head producing thousands of conidia.¹¹ Inhalation of conidia by immunocompetent persons rarely causes clinical disease, because the innate immune system readily eliminates the conidia.²² However, with the increase in numbers of immunosuppressed patients, this fungus has become the most prevalent airborne fungal pathogen in developed countries.¹²A persistently neutropenic rabbit model of invasive pulmonary aspergillosis has been developed to study potential advances in diagnosis, treatment, and prevention of A. fumigatus.^3,8 For example, this model has been used to demonstrate the benefits of using ultrafast computerized tomography to improve timely identification and monitoring of infection with A. fumigatus.^20,26 A novel PCR assay for invasive pulmonary aspergillosis that was developed by using this model is now a clinical molecular diagnostic test.^13,27 In addition, this model has been used to validate an enzyme immunoassay for galactomannan, a component of the fungal cell well that is now used as a biomarker for infection.⁷ Numerous studies have been performed investigating a variety of treatments for A. fumigatus, including liposomal amphotericin B, voriconazole, caspofungin, and various combination protocols involving echinocandins, polyenes, and triazoles.^8,9,14,17-19On our submission of an animal use protocol, we were requested to perform an environmental surveillance study to ascertain whether persistently neutropenic rabbits shed infectious fungal elements after the animals are infected intratracheally with A. fumigatus conidia. Despite its environmental ubiquity, A. fumigatus is classified as a BSL2 pathogen.⁵ Although our laboratory handles this organism on culture medium within a biologic safety cabinet to prevent propagation of conidia, our initial studies indicated that rabbits intratracheally inoculated with A. fumigatus for the establishment of experimental invasive aspergillosis did not shed conidia and could be handled under ABSL1 conditions.     

Associations between neck musculoskeletal complaints and work related factors among public service computer workers in Kaunas

Objectives

Information technologies have been developing very rapidly, also in the case of occupational activities. Epidemiological studies have shown that employees, who work with computers, are more likely to complain of musculoskeletal disorders (MSD). The aim of this study was to evaluate associations between neck MSD and individual and work related factors.

Materials and Methods

The investigation which consisted of two parts — a questionnaire study (using Nordic Musculoskeletal questionnaire and Copenhagen Psychosocial Questionnaire) and a direct observation (to evaluate ergonomic work environment using RULA method) was carried out in three randomly selected public sector companies of Kaunas. The study population consisted of 513 public service office workers.

Results

The survey showed that neck MSDs were very common in the investigated population. The prevalence rate amounted to 65.7%. According to our survey neck MSDs were significantly associated with older age, bigger work experience, high quantitative and cognitive job demands, working for longer than 2 h without taking a break as well as with higher ergonomic risk score. The fully adjusted model working for longer than 2 h without taking a break had the strongest associations with neck complaints.

Conclusion

It was confirmed, that neck MSDs were significantly associated with individual factors as well as conditions of work, therefore, preventive actions against neck complaints should be oriented at psychosocial and ergonomic work environment as well as at individual factors.