Systematic review: occupational physical activity and low back pain.

BACKGROUND: Although various occupational physical activities are suspected of contributing to low back pain (LBP), causal relationships have not been confirmed, complicating adjudication of work injuries, return to work instructions and preventive efforts. AIMS: To summarize eight systematic review (SR) reports that examined evidence supporting causal relationships between bending/twisting, awkward postures, sitting, standing/walking, carrying, pushing/pulling, lifting and manual handling/assisting patients and LBP. METHODS: A literature search was conducted to identify eligible studies. Methodological quality was assessed using a modified Newcastle-Ottawa Scale (NOS). Levels of evidence supporting factors for causation were examined using a Bradford Hill framework. Results were presented in eight SR reports, each focused on one or more related physical activities. This study summarizes findings from those reports and offers clinicians an overview. RESULTS: Collectively, the eight SR reports included 99 studies. None found strong evidence supporting a causal relationship between any occupational physical activity considered and LBP. Conflicting evidence was found between LBP and bending, twisting, lifting or pushing/pulling, but only for statistical association, not causation. Strong evidence against a causal relationship was found between LBP and manual handling/assisting patients, awkward postures, carrying, sitting, standing or walking. CONCLUSIONS: Although occupational physical activities are suspected of causing LBP, findings from the eight SR reports did not support this hypothesis. This may be related to insufficient or poor quality scientific literature, as well as the difficulty of establishing causation of LBP. These population-level findings do not preclude the possibility that individuals may attribute their LBP to specific occupational physical activities.

Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: a strategy for the design of peptidase inhibitors.

The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase which has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO(3)H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH(2). In seeking a reversible inhibitor of this peptidase, the enzymatic binding subsites were characterized using a fluorimetric assay based on the hydrolysis of the artificial substrate Ala-Ala-Phe-amidomethylcoumarin. A series of di- and tripeptides having various alkyl or aryl side chains was studied to determine the accessible volume for binding and to probe the potential for hydrophobic interactions. From this initial study the tripeptides Ile-Pro-Ile-OH (K(i) = 1 microM) and Ala-Pro-Ala-OH (K(i) = 3 microM) and dipeptide amide Val-Nvl-NHBu (K(i) = 3 microM) emerged as leads. Comparison of these structures led to the synthesis of Val-Pro-NHBu (K(i) = 0.57 microM) which served for later optimization in the design of butabindide, a potent reversible competitive and selective inhibitor of the CCK-8-inactivating peptidase. The strategy for this work is explicitly described since it illustrates a possible general approach for peptidase inhibitor design.

Characterization and inhibition of a cholecystokinin-inactivating serine peptidase.

A cholecystokinin (CCK)-inactivating peptidase was purified and identified as a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10), a cytosolic subtilisin-like peptidase of previously unknown functions. The peptidase was found in neurons responding to cholecystokinin, as well as in non-neuronal cells. Butabindide, a potent and specific inhibitor, was designed and shown to protect endogenous cholecystokinin from inactivation and to display pro-satiating effects mediated by the CCKA receptor.

Poly(binaphthyl-20-crown-6) as receptor based molecular selective potentiometric electrodes for catecholamines and other 1,2-dihydroxybenzene derivatives.

A novel type of poly(crown ether) electrode that is capable of selectively determining some 1,2-dihydroxybenzenes has been developed. A lipophilic macrocyclic crown ether, binaphthyl-20-crown-6, is electrochemically deposited on a platinum disc electrode. The film obtained is used as a sensory element for a potentiometric electrode for the determination of some neurotransmitters, namely, catecholamines. The new electrode is also capable of discriminating the steric shapes of 1,2-dihydroxybenzene moieties. The response of the new electrode is based on the principle of 'host-guest' chemistry. The potentiometric response is dependent on the pH of the solution and the nature of the buffer medium. The new sensor electrode has a useful analytical range of 1.5 x 10(-8) M-2 x 10(-5) M with a linear dynamic range between about 1 x 10(-7) M-5 x 10(-4) M with a 'super-Nernstian' slope of 110-130 mV/decade. The detection limit in phosphate buffer (0.1 M, pH 9.4) is ca. 3 x 10(-8) M for catecholamine. The sensor electrode is virtually insensitive towards interference from most inorganic ions and circumvents the interference from ascorbic acid, which is often found using amperometric methods in biological samples. A partial response mechanism of the present electrode is discussed, supported by results of electron dispersive analysis by x-rays (EDAX).

Abnormal joint mechanics and the proteoglycan composition of normal and healing rabbit medial collateral ligament.

OBJECTIVE: This study investigated the influence that abnormal joint mechanics may have upon the biochemical composition of the joint's own soft tissue holding elements. DESIGN: The investigation used an animal model of ligament injury, the rabbit medial collateral ligament (MCL). The proteoglycan component of the ligament extracellular matrix was extracted, purified and characterized. INTERVENTIONS: The experimental groups consisted of: a) a control group consisting of the MCL from both right and left knees of six animals that had not undergone surgery; b) a group (healing gap injury) of six MCL from right knees in which a segment of tissue had been excised from the anterior cruciate and the MCL of the right knee 3 wk prior to sacrifice; and c) a third group (contralateral gap injury) comprised of the MCL from the six left knees of the same gap injury animals. OUTCOME MEASURES: The MCL water content, total proteoglycan content, hexose and hexuronate-containing proteoglycan and proteoglycan electrophoretic mobility were determined for each group studied. RESULTS: The healing gap injury MCL was found to have a higher water content, a higher total proteoglycan content and a higher proportion of aggregating proteoglycan than MCL from control animals. The nonaggregating proteoglycan fraction from the contralateral MCL (group 3) had a greater electrophoretic mobility and probably, therefore, a smaller molecular weight than that found in the MCL from the same knee of control animals. CONCLUSIONS: Since MCL healing took place in an abnormal mechanical environment, these results suggest that joint biomechanics may be an important factor in mediating connective tissue proteoglycan composition.

The proteoglycans of the cartilaginous end-plate of the human intervertebral disc change after maturity.

Lumbar spines collected postmortem were assigned to one of two groups: group 1--three spines with healthy discs, or group 2--three spines with severely degenerated discs. The proteoglycans (PGs) of the cartilaginous end-plate (CEP) were extracted with 4 M guanidinium chloride containing protease inhibitors and were purified by caesium chloride density gradient ultracentrifugation. On Sepharose CL-2B chromatography, the most dense 20% of the gradient (the A1 fraction) showed two subfractions, one eluting near the void volume and one partitioned by the gel. Both fractions resembled those of the nucleus pulposus and the anulus fibrosus in the number of components seen on agarose-polyacrylamide gel electrophoresis. Both fractions changed with ageing/degeneration; the ratio of keratan sulphate to chondroitin sulphate, which was about 1 in group 1, increased to about 3 in group 2; the hydrodynamic volumes fell; the electrophoretically distinguishable component of lowest mobility disappeared while new, highly mobile components appeared; and the water content decreased slightly. Clearly, the PGs of the CEP of degenerated intervertebral discs differed from those of healthy discs; this supports the view that the CEP participates in the process of ageing/degeneration in the disc.

17 alpha-Z-[125I]iodovinyloestradiol and its 3-acetate: chemical synthesis in vivo distribution studies in the rat. Comparison of tissue accumulation and metabolic stability with 17 alpha-E-[125I]iodovinyl and 16 alpha-[125I]iodo oestradiols.

Certain oestrogens on substitution with halogens, have been shown to retain receptor binding affinity and accumulate in target tissues and therefore could, when labelled with gamma-emitting halogen isotope, act as radiopharmaceuticals for the imaging of receptor positive breast tumours. In order to evaluate putative radiopharmaceuticals, 17 alpha-Z-iodovinyloestradiol ((17 alpha,20Z)-21-iodo-19-norpregna-1,3,5(10),20-tetraene-3,17 beta-diol) and its 3-acetate have been chemically synthesized and labelled with 125I. Tissue distribution studies in female rats have been compared to those obtained using 17 alpha-E-[125I]iodovinyloestradiol ((17 alpha,20E)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17 beta-diol) and its 3-acetate and to 16 alpha-[125I]iodo oestradiol (1,3,5(10)-estratien-16 alpha-[125I]iodo-3,17 beta-diol). All compounds showed a similar tissue distribution with the highest concentrations (cpm/g tissue) in the thyroid greater than liver greater than uterus greater than kidney greater than lung greater than blood greater than heart, spleen. The concentration in the uterus was highest after injection of 17 alpha-Z-iodovinyloestradiols or 16 alpha-iodo oestradiol. Target (uterus) to background (blood) tissue ratios were highest after injection of 17 alpha-Z-iodovinyloestradiol-3-acetate and 16 alpha-iodo oestradiol (6:1). Deiodination in vivo took place to a small degree, amounting to 1.6%, 0.9% and 0.35% of the injected dose after 4 hr with the 17 alpha-Z, 17 alpha-E and 16 alpha compounds, respectively. For reasons of chemical expediency and consideration of the biological results 17 alpha-Z-iodovinyloestradiol-3-acetate is the compound of choice for the detection of oestrogen receptor positive tissues.

Preliminary evaluation of a scheme for grading the gross morphology of the human intervertebral disc.

A five-category grading scheme for assessing the gross morphology of midsagittal sections of the human lumbar intervetebral disc was developed. The ability of three observers to categorize a series of 68 discs with a wide spectrum of morphologies established the comprehensiveness of the classification. Three independent observers tested the reproducibility of the procedure by assignment of grades blindly to duplicate images of 68 discs taken from 15 spines. The intraobserver agreement ranged from 87 to 91%. The interobserver agreement was 61, 64, and 88% for the three pairs, the two low values being attributable to the bias of one observer. The agreement between the assigned and average grades was 85, 92, 68, 90, and 76% for Grades I through V, respectively. Except for Grade III, the disagreements were attributable mainly to the bias of one observer. Both the increase in the grade with age and the finding that all the discs within 14 of 15 spines had a narrow range of grades demonstrated the biologic credibility of the scheme.

Proteoglycans and degenerative spondylosis.

Proteoglycans are high molecular weight glycoproteins found in connective tissue. They imbibe water into intervertebral disc and apophyseal joint articular cartilage, endowing the tissues with elasticity and compressibility. A decrease in total tissue content of proteoglycans appears to predispose intervertebral disc to degeneration. The earliest tissue changes associated with the onset of spondylosis occur at the molecular level and may include alterations in proteoglycan structure and content. A number of models have been suggested to describe the relationship between changes in proteoglycan composition and degenerative changes in cartilage and intervertebral disc.

An inhibitor of ornithine decarboxylase in lactogen-deprived Nb2 node rat lymphoma cells.

A previous study has shown that the activity of ornithine decarboxylase in cultured Nb2 node rat lymphoma cells falls to undetectable levels when cells become quiescent following incubation in lactogen (prolactin)-deficient medium. In the present study, it was found that addition of extracts of the lactogen-deprived, quiescent cells to extracts of log-phase cells markedly reduced the ornithine decarboxylase activity of the latter, the inhibitory activity being proportional to the amount of quiescent cell extract added. Evidence is presented that the ornithine decarboxylase-inhibitory activity in the quiescent cell extracts is due to an antizyme-like, polypeptide factor with an Mr of approx. 28,000. The activity of the inhibitor appears to be directed rather specifically against ornithine decarboxylase, since the activities of S-adenosylmethionine decarboxylase, thymidine kinase and uridine kinase were not affected. The Nb2 cell ornithine decarboxylase inhibitor may have an important role in modulating the cellular levels of ornithine decarboxylase as they change in response to the withdrawal and restoration of extracellular mitogenic lactogens.

An inhibitor of ornithine decarboxylase in the thymus and spleen of dexamethasone-treated rats.

A marked decrease in activity of ornithine decarboxylase in thymus and spleen occurs soon after treatment of rats with a glucocorticoid. In the present study, evidence was obtained that extracts of these tissues prepared 5 h after administration of dexamethasone, when the enzyme activity is very low, contain an inhibitor of ornithine decarboxylase. The inhibitor is also present at 12 h after treatment and, in lesser amount, at 2.5 h, but was not evident at 24 h. The inhibitory activity was destroyed by treatment with heat or with trypsin, and was not lost on dialysis of the extract. Preliminary experiments indicate that the Mr of the inhibitor is greater than 50 000, which differentiates it from antizyme, an inhibitor of ornithine decarboxylase found in several other cell types. The inhibitor seems to act by a non-catalytic and non-competitive mechanism. The inhibition is dependent on the amount of inhibitor and does not change with time. Since inhibition is not changed by dialysis of the inhibitory extract, its activity apparently does not require small-Mr substances. This differentiates it from inhibitors which inactivate ornithine decarboxylase by covalent modification, such as the polyamine-dependent protein kinase or transglutaminase. The formation of this inhibitor is an early event in lymphoid tissues in response to dexamethasone and may be important in causing the inhibition of cell division which precedes the destruction of lymphocytes.