Psychosocial work environment and sickness absence among British civil servants: the Whitehall II study

OBJECTIVES: This study sought to examine the association between the psychosocial work environment and subsequent rates of sickness absence. METHODS: The analyses were based on a cohort of male and female British civil servants (n=9072). Rates of short spells (7 days) of sickness absence were calculated for different aspects of the psychosocial work environment, as measured by self-reports and personnel managers' ratings (external assessments). RESULTS: Low levels of work demands, control, and support were associated with higher rates of short and long spells of absence in men and, to a lesser extent, in women. The differences were similar for the self-reports and external assessments. After adjustment for grade of employment, the differences were diminished but generally remained significant for short spells. The combination of high demands and low control was only associated with higher rates of short spells in the lower grades. CONCLUSIONS: The psychosocial work environment predicts rates of sickness absence. Increased levels of control and support at work could have beneficial effects in terms of both improving the health and well-being of employees and increasing productivity.     

Molecular characterization of a Campylobacter jejuni lipoprotein with homology to periplasmic siderophore-binding proteins

A genomic library of Campylobacter jejuni (NCTC 11351) was used to identify genes which could confer a hemolytic phenotype to Escherichia coli. Accordingly, when transformants were screened on blood plates, hemolytic colonies appeared at a frequency of 3 x 10(-4). The gene conferring the hemolytic activity was identified by subcloning and was found to be responsible for the phenotype of all hemolytic transformants isolated. The open reading frame conferring this activity encodes a protein of 36,244 Da with a typical endopeptidase type II leader sequence. The protein is modified with palmitic acid when it is processed in E. coli, confirming that it is a typical lipoprotein. The deduced gene product of 329 amino acids has significant homology to the group of solute binding proteins from periplasmic-binding-protein-dependent transport systems for ferric siderophores, including the FatB protein from Vibrio anguillarium and the FhuD protein from Bacillus subtilis. In particular, the protein contained the signature sequence for siderophore-binding proteins, suggesting that the protein may be the siderophore-binding protein component of an iron acquisition system of C. jejuni.     

Clinical efficacy of the amplified Mycobacterium tuberculosis direct test for the diagnosis of pulmonary tuberculosis

The amplified Mycobacterium tuberculosis direct test (MTD) is a rapid diagnostic test based on a nucleic acid amplification technique, which can be used directly on processed clinical specimens. We evaluated the clinical utility of the MTD for diagnosing pulmonary tuberculosis by comparing the sensitivity and specificity of the test with acid-fast smear, mycobacterial culture, and clinical evaluation. The study included 844 respiratory tract specimens from 421 patients, which were submitted to the microbiology laboratory of our urban teaching hospital over a 6-mo period. Compared with culture, MTD had a sensitivity of 93.6% and specificity of 97.8%. MTD was more sensitive in detecting pulmonary tuberculosis in patients with previously undiagnosed disease (74.7%) than in those with established disease receiving chemotherapy (29.2%), and in smear-positive (95.5%) than in smear-negative (70.0%) disease. There were two false positive MTD results in patients with nontuberculous mycobacteria, for a specificity in this population of 97.3%. We conclude that MTD, when used in conjunction with routine smear and culture, is a useful rapid diagnostic test for suspected pulmonary tuberculosis.     

A role of Hsp60 in autoimmune diabetes: analysis in a transgenic model

A pathogenic role for self-reactive cells against the stress protein Hsp60 has been proposed as one of the events leading to autoimmune destruction of pancreatic beta cells in the diabetes of nonobese diabetic (NOD) mice. To examine this hypothesis, we generated transgenic NOD mice carrying a murine Hsp60 transgene driven by the H-2E alpha class II promoter. This would be expected to direct expression of the transgene to antigen-presenting cells including those in the thymus and so induce immunological tolerance by deletion. Detailed analysis of Hsp60 expression revealed that the endogenous gene is itself expressed strongly in thymic medullary epithelium (and weakly in cortex) yet fails to induce tolerance. Transgenic mice with retargeted Hsp60 showed overexpression of the gene in thymic cortical epithelium and in bone marrow-derived cells. Analysis of spontaneous T-cell responses to a panel of self and heterologous Hsp60 antigens showed that tolerance to the protein had not been induced, although responses to an immunodominant 437-460 epitope implicated in disease were suppressed, probably indicating an epitope shift. This correlated with changes in disease susceptibility: insulitis in transgenic mice was substantially reduced so that pathology rarely progressed beyond periislet infiltration. This was reflected in a substantial reduction in hyperglycemia and disease. These data indicate that T cells specific for some epitopes of murine Hsp60 are likely to be involved in the islet-cell destruction that occurs in NOD mice.     

The diagnosis and management of gastroesophageal reflux disease

GERD is a common clinical problem. Generally, its clinical presentation and management are straightforward. Greater awareness of the numerous extraesophageal manifestations of the disease aids patients and physicians in appropriate recognition and treatment. Medical therapy is effective in the majority of cases but often requires long-term medication for acceptable symptom control. A small, but significant proportion of patients presents with or develops complications of GERD, most importantly Barrett's esophagus. Although the logistics of long-term surveillance of persons with Barrett's esophagus is unclear, the association of this metaplastic change with esophageal adenocarcinoma underscores the importance of regular follow-up.     

Itraconazole resistance in Aspergillus fumigatus

Invasive aspergillosis is an increasingly frequent opportunistic infection in immunocompromised patients. Only two agents, amphotericin B and itraconazole, are licensed for therapy. Itraconazole acts through inhibition of a P-450 enzyme undertaking sterol 14alpha demethylation. In vitro resistance in Aspergillus fumigatus to itraconazole correlated with in vivo outcome has not been previously described. For three isolates (AF72, AF90, and AF91) of A. fumigatus from two patients with invasive aspergillosis itraconazole MICs were elevated. A neutropenic murine model was used to establish the validity of the MICs. The isolates were typed by random amplification of polymorphic DNA. Analysis of sterols, inhibition of cell-free sterol biosynthesis from [14C] mevalonate, quantitation of P-450 content, and [3H]itraconazole concentration in mycelial pellets were used to determine the mechanisms of resistance. The MICs for the three resistant isolates were >16 microg/ml. In vitro resistance was confirmed in vivo for all three isolates. Molecular typing showed the isolates from the two patients to be genetically distinct. Compared to the susceptible isolate from patient 1, AF72 had a reduced ergosterol content, greater quantities of sterol intermediates, a similar susceptibility to itraconazole in cell-free ergosterol biosynthesis, and a reduced intracellular [3H]itraconazole concentration. In contrast, AF91 and AF92 had slightly higher ergosterol and lower intermediate sterol concentrations, fivefold increased resistance in cell-free systems to the effect of itraconazole on sterol 14alpha demethylation, and intracellular [3H] itraconazole concentrations found in susceptible isolates. Resistance to itraconazole in A. fumigatus is detectable in vitro and is present in wild-type isolates, and at least two mechanisms of resistance are responsible.     

Molecular cloning and expression of palmitoyl-protein thioesterase 2 (PPT2), a homolog of lysosomal palmitoyl-protein thioesterase with a distinct substrate specificity

Palmitoyl-protein thioesterase is a lysosomal hydrolase that removes long chain fatty acyl groups from modified cysteine residues in proteins. Mutations in this enzyme were recently shown to underlie the hereditary neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis, and lipid thioesters derived from acylated proteins were found to accumulate in lymphoblasts from individuals with the disorder. In the current study, we describe the cloning and expression of a second lysosomal thioesterase, palmitoyl-protein thioesterase 2 (PPT2), that shares an 18% identity with palmitoyl-protein thioesterase. Transient expression of a PPT2 cDNA led to the production of a glycosylated lysosomal protein with palmitoyl-CoA hydrolase activity comparable with palmitoyl-protein thioesterase. However, PPT2 did not remove palmitate groups from palmitoylated proteins that are substrates for palmitoyl-protein thioesterase. In cross-correction experiments, PPT2 did not abolish the accumulation of protein-derived lipid thioesters in palmitoyl-protein thioesterase-deficient cell lines. These results indicate that PPT2 is a lysosomal thioesterase that possesses a substrate specificity that is distinct from that of palmitoyl-protein thioesterase.