Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial.

OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and the second most common cause of long-term disability among middle-aged and older adults in the United States. Methylsulfonylmethane (MSM) is a popular dietary supplement used as a single agent and in combination with other nutrients, and purported to be beneficial for arthritis. However, there is paucity of evidence to support the use of MSM. METHODS: A randomized, double-blind, placebo-controlled trial was conducted. Fifty men and women, 40-76 years of age with knee OA pain were enrolled in an outpatient medical center. Intervention was MSM 3g or placebo twice a day for 12 weeks (6g/day total). Outcomes included the Western Ontario and McMaster University Osteoarthritis Index visual analogue scale (WOMAC), patient and physician global assessments (disease status, response to therapy), and SF-36 (overall health-related quality of life). RESULTS: Compared to placebo, MSM produced significant decreases in WOMAC pain and physical function impairment (P<0.05). No notable changes were found in WOMAC stiffness and aggregated total symptoms scores. MSM also produced improvement in performing activities of daily living when compared to placebo on the SF-36 evaluation (P<0.05). CONCLUSION: MSM (3g twice a day) improved symptoms of pain and physical function during the short intervention without major adverse events. The benefits and safety of MSM in managing OA and long-term use cannot be confirmed from this pilot trial, but its potential clinical application is examined. Underlying mechanisms of action and need for further investigation of MSM are discussed.

Working with older people with communication difficulties: an evaluation of care worker training.

Studies suggest that a high proportion of older people in residential and nursing care have communication difficulties and there is some awareness of the need for staff training to allow effective communication to be achieved. This paper describes part of the evaluation of a one-day training package aimed at enabling care staff to communicate with older people who have a variety of communication difficulties. Care staff from four partner agencies completed questionnaires pre- and post-training, addressing contact with people with communication disorders, previous training on communication, knowledge about communication, attitudes towards communication problems and strategies to help communication with people who have communication difficulties. Positive gains were found in attitudes and self-perceptions of knowledge and competence, as well as in appropriate citations of strategies to enhance communication. The findings are discussed with reference to the need for enhanced communication skills in care workers engendered by current developments in care policy.

Speech and language therapists as trainers: enabling care staff working with older people.

A recently completed evaluation of a one day training package on communication has found evidence of a perceived need for training in both communication and communication impairment among care workers employed by health and social care agencies. This paper is a discussion of the factors that contribute to the delivery of successful workshops to front line care workers.

Perception of ecological risk to water environments.

This paper examines lay and expert perceptions of the ecological risks associated with a range of human activities that could adversely affect water resource environments. It employs the psychometric paradigm pioneered in characterizing perceptions of human health risks, which involves surveys to obtain judgments from subjects about risk items in terms of several important characteristics of the risks. The paper builds on a previous study that introduced ecological risk perception. This second study employs a larger, more diverse sample, a more focused topic area, and comparisons between lay and expert judgments. The results confirm that a small set of underlying factors explain a great deal of variability in lay judgments about ecological risks. These have been termed Ecological Impact, Human Benefits, Controllability, and Knowledge. The results are useful in explaining subjects' judgments of the general riskiness of, and need for regulation of, various risk items. The results also indicate several differences and areas of agreement among the lay and expert samples that point to potential key issues in future ecological risk management efforts for water resources.

The relationship between plasma insulin level, prostaglandin production by adipose tissue, and blood pressure in normal rats and rats with diabetes mellitus and diabetic ketoacidosis.

There is a correlation between circulating insulin levels and blood pressure over a wide range of insulin levels and in a variety of clinical conditions. Production of prostaglandin (PG)E(2) (PGE(2)) and prostacyclin (PGI(2)), two potent vasodilators, by adipose tissue is increased in severe insulin deficiency, eg, diabetic ketoacidosis (DKA), explaining the decreased peripheral vascular resistance in DKA. Conversely, decreased production of PGE(2) and PGI(2) may mediate the relationship between hyperinsulinemia and hypertension. Although insulin inhibits PG production in normal rat adipose tissue, PG production in adipose tissue from patients or experimental animals with nonketotic diabetes mellitus (DM) and DKA has not been studied. We examined the effect of plasma insulin levels on blood pressure and on adipose tissue PG production in rats with DM and DKA and normal rats. There was a significant relationship between plasma insulin level and blood pressure in rats with DM and normal controls (P < .021) and in rats with DKA and normal controls (P < .0001). There was an inverse linear correlation between plasma insulin levels and basal 6-keto-PGF(1 alpha) production by a mixture of adipocytes and endothelial cells from epididymal adipose tissue in rats with DKA and normal rats (P < .0252, R2 = .67). Rates of basal glycerol, PGE(2), and 6-keto-PGF(1alpha) production by a mixture of adipocytes and endothelial cells from epididymal adipose tissue were significantly higher in rats with DKA than in normal rats. These rates were also higher in rats with DM than in normal rats, but only glycerol values were statistically significant. In rats with DM, PGE(2) production induced by epinephrine 2 x 10(-5) mol/L (but not lower concentrations) was significantly greater than basal production (P < .05); production of 6-keto-PGF(1alpha) was not stimulated. In rats with DKA, 6-keto-PGF(1alpha) production induced by epinephrine 2 x 10(-5) mol/L (but not lower concentrations) was significantly greater than basal production (P < .05); production of PGE(2) was not stimulated. We conclude the following: (1) there is a close correlation between circulating insulin level and systemic blood pressure when rats with DM and DKA are compared with controls; (2) in insulin deficiency, PGI(2) and PGE(2) production are increased in adipose tissue versus normal tissue; and (3) the correlation between insulin level and blood pressure may be mediated by the inhibitory effect of insulin on vasodilative PG production by adipose tissue.

Characterizing perception of ecological risk.

Relatively little attention has been paid to the role of human perception and judgment in ecological risk management. This paper attempts to characterize perceived ecological risk, using the psychometric paradigm developed in the domain of human health risk perception. The research began by eliciting a set of scale characteristics and risk items (e.g., technologies, actions, events, beliefs) from focus group participants. Participants in the main study were 68 university students who completed a survey instrument that elicited ratings for each of 65 items on 30 characteristic scales and one scale regarding general risk to natural environments. The results are presented in terms of mean responses over individuals for each scale and item combination. Factor analyses show that five factors characterize the judgment data. These have been termed: impact on species, human benefits, impact on humans, avoidability, and knowledge of impacts. The factor results correspond with initial expectations and provide a plausible characterization of judgments regarding ecological risk. Some comparisons of mean responses for selected individual items are also presented.

Effects of a small quantity of omega-3 fatty acids on cardiovascular risk factors in NIDDM. A randomized, prospective, double-blind, controlled study.

OBJECTIVE: To study the effects of a low dose of omega-3 fatty acids on platelet function and other cardiovascular risk factors in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: We performed a randomized, prospective, double-blind, controlled study of a low dose of omega-3 fatty acids (2.5 g/day) in 20 ambulatory subjects with NIDDM. Subjects ingested five 1-g fish oil capsules each containing 0.5 g omega-3 fatty acids or five 1-g safflower oil capsules per day for 6 weeks followed by a 6-week washout period. RESULTS: Nine subjects completed the study in each group. Both groups exhibited moderate control of glucose levels; modest elevations in baseline total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels; and normal blood pressure values. In the fish oil group, plasma omega-3 fatty acid levels increased significantly. Fish oil significantly reduced the slope of the dose-response curves for collagen-induced platelet aggregation to one-third the value observed with safflower oil. No difference was observed in collagen-induced production of thromboxane A2 (TXA2, measured as the stable derivative TXB2), or in adenosine-5'-diphosphate- (ADP) induced platelet aggregation or TXA2 generation. Patients with high initial collagen-induced platelet TXA2 production showed a significantly larger drop after fish oil than safflower oil. Fish oil significantly reduced TG levels by 44 mg/dl and decreased upright systolic blood pressure (sBP) by 8 mmHg compared with safflower oil. Fish oil caused a significant but small increase in HbA1c (0.56%) and total cholesterol (20 mg/dl) but had no effect on fasting glucose, high-density lipoprotein cholesterol, or LDL-cholesterol levels. CONCLUSIONS: Small doses of fish oil inhibit platelet aggregation and TXA2 production, reduce upright sBP and TG levels, and have only a small effect on glucose and cholesterol levels in patients with moderately controlled NIDDM. Small quantities of omega-3 fatty acids or dietary fish are safe and potentially beneficial in NIDDM patients.

Coordinate control of lipolysis by prostaglandin E2 and prostacyclin in rat adipose tissue.

PGE2 is a potent antilipolytic agent produced by adipose tissue, but its role as a physiological regulator of triglyceride lipolysis is controversial because inhibitors of prostaglandin synthesis have not enhanced hormone-stimulated lipolysis in adipose tissue consistently. Adipose tissue also produces PGI2, but this eicosanoid has not had a demonstrated effect on lipolysis under physiological conditions previously. We investigated both PGE2 and PGI2 production and their effects on lipolysis in rat adipose tissue. We found that 1) EPI-stimulated PGE2 production (like PGI2 production) requires the cooperation of adipocytes and endothelial cells, 2) adipose tissue produces PGE2 and PGI2 at comparable rates, 3) indomethacin inhibits EPI-induced PGE2 and PGI2 production and has no effect on EPI-stimulated lipolysis when added to a mixture of adipocytes and endothelial cells or to intact epididymal fat pads, 4) PGI2 is a potent lipolytic agent when added to isolated adipocytes in the absence of endothelial cells under physiological conditions, 5) the magnitudes and the ED50s of the antilipolytic effect of PGE2 and the lipolytic effect of PGI2 in isolated adipocytes in the absence of endothelial cells are comparable, 6) PGI2 antagonizes the antilipolytic effect of PGE2 in isolated adipocytes in the absence of endothelial cells in a dosage-related manner, and 7) the antilipolytic effect of added PGE2 in isolated adipocytes is greater in the absence of endothelial cells than in their presence, suggesting that endogenous eicosanoid production reduces the effectiveness of added PGE2. These studies demonstrate that catecholamine-induced lipolysis is under the coordinate control of PGE2, a potent antilipolytic agent, and PGI2, a potent lipolytic agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin, prostaglandins, and the pathogenesis of hypertension.

Hypertension is associated with hyperinsulinemia in the presence or absence of obesity or glucose intolerance. Physiological concentrations of insulin decrease the catecholamine-induced production of prostaglandin I2 (PGI2; prostacyclin) and PGE2, two potent vasodilators, in adipose tissue, one of the largest organs in the body. This finding suggests that hyperinsulinemia increases peripheral vascular resistance and blood pressure by inhibiting the stimulatory effect of adrenergic agonists (and perhaps other agonists) on the production of PGI2 and PGE2 in adipose tissue (and perhaps other tissues). This concept is supported by evidence that PGI2 and PGE2 modulate vascular reactivity in states of health and disease. For example, during insulin deficiency, i.e., in diabetic ketoacidosis, PGI2 and PGE2 production by adipose tissue are increased, and peripheral vascular resistance and blood pressure are decreased. This hypothesis is also supported by evidence that blood flow through rat and human adipose tissue is decreased in obesity and that insulin decreases the blood flow through adipose tissue in nonobese rats. Thus, insulin may regulate PGI2 and PGE2 production by adipose tissue (and possibly other tissues) through a wide range of concentrations with important physiological and clinical consequences.

Prostacyclin and pathogenesis of hemodynamic abnormalities of diabetic ketoacidosis in rats.

The pathogenesis of the hemodynamic abnormalities of diabetic ketoacidosis (DKA) is not well understood. Previous studies suggest that prostacyclin (PGI2) production by adipose tissue is increased in DKA. We investigated the role of PGI2 in the pathogenesis of the reduced vascular resistance in DKA. Rats with streptozocin-induced DKA were anesthetized with pentobarbital sodium, and flow was measured with an electromagnetic probe on the infradiaphragmatic aorta. The plasma level of 6-keto-PGF1 alpha (stable derivative of PGI2) was higher (mean +/- SE 0.91 +/- 0.05 ng/ml) and vascular resistance lower (4.9 +/- 0.2 mmHg.ml-1.min-1.100 g-1 [resistance units, RU]) in 67 rats with DKA than in 21 normal rats (0.34 +/- 0.03 ng/ml, P less than .01, and 9.0 +/- 0.7 RU, P less than .01, respectively). Inhibition of cyclooxygenase activity with either indomethacin or meclofenamic acid reduced the plasma 6-keto-PGF1 alpha level but failed to raise vascular resistance. Infusions of PGI2 in rats with DKA demonstrated that the vasculature was responsive to PGI2. Inhibition of cyclooxygenase activity not only reduced PGI2 production but also suppressed renin release. When the effects of the renin-angiotensin system were excluded by bilateral nephrectomy, indomethacin caused a significant increase (P less than .05) in vascular resistance. Thus, the failure of cyclooxygenase inhibitors to raise vascular resistance in DKA was a result of concurrent suppression of vasodilator (PGI2) and vasoconstrictor (renin-angiotensin system) mechanisms that are activated in DKA. Insulin administration increased vascular resistance (P less than .01) and decreased the level of plasma 6-keto-PGF1 alpha (P less than .01). Combined administration of PGI2 and insulin did not alter vascular resistance, suggesting that the increase in vascular resistance with insulin was predominantly due to the reduction of circulating PGI2. Thus, vascular resistance is decreased in DKA primarily as a result of the vasodilator effects of PGI2 produced by adipose tissue. The activation of the renin-angiotensin system represents a partial compensation. The increase in PGI2 production may contribute to the hypotension and mortality of DKA.

Cooperation of adipocytes and endothelial cells required for catecholamine stimulation of PGI2 production by rat adipose tissue.

Disturbances of prostaglandin I2 (PGI2, prostacyclin) production by adipose tissue contribute to the pathogenesis of diabetic ketoacidosis and may contribute to the pathogenesis of hypertension and vascular disease. We studied the cellular basis of PGI2 production in adipose tissue, measured as release of 6-keto-PGF1 alpha in response to epinephrine. Adipocytes did not produce PGI2 when nonfat cells were removed by repeated washing. The nonadipocyte cellular constituents of adipose tissue (nonfat cells) did not produce PGI2 in the absence of adipocytes. Both adipocytes and nonfat cells were required for PGI2 production in response to epinephrine. Adipocytes pretreated with 0.2 mM aspirin to inhibit PGH synthase nevertheless promoted PGI2 production when mixed with nonfat cells. Nonfat cells preincubated with aspirin did not produce PGI2 when mixed with adipocytes. The nonfat cells converted arachidonic acid to PGI2 but adipocytes did not. Epinephrine stimulated lipolysis and PGI2 production in a dose-dependent parallel manner, but the responses were distinct above 10(-6) M. Characterization of the nonfat cells by fractionation on a Percoll density gradient followed by measurement of angiotensin-converting enzyme activity and 6-keto-PGF1 alpha production indicated that the nonfat cells were predominantly vascular endothelial cells. We conclude that catecholamine-stimulated PGI2 production in adipose tissue results from the cooperation of adipocytes and vascular endothelial cells. The adipocytes provide arachidonic acid, which is converted to PGI2 by the vascular endothelial cells. Because adipose tissue is located near blood vessels throughout the body, adipocytes may be an important source of arachidonic acid for vascular endothelial cells in various circumstances in health and disease. Our findings raise the possibility that adipocytes may, under some circumstances, release arachidonic acid into the systemic circulation where it is used by vascular endothelial cells throughout the body to produce PGI2 and other eicosanoids.

Omega-3 fatty acids in diabetes mellitus. Gift from the sea?

The potential role of omega-3 fatty acids in the prevention of atherosclerotic disease in the nondiabetic population currently engenders interest, enthusiasm, and controversy. Some apparently beneficial effects of omega-3 fatty acids on platelet function, eicosanoid formation, plasma triglyceride levels, and blood pressure have been described in patients with diabetes mellitus. However, enthusiasm for the use of omega-3 fatty acids in diabetes has been dampened by reports of potentially deleterious effects of these agents, including increased plasma glucose, glycosylated hemoglobin, plasma total cholesterol and LDL cholesterol, and serum apolipoprotein B levels. These adverse effects have been achieved with large, perhaps excessive, doses of omega-3 fatty acids, in the range of 4-10 g/day. The magnitude of these adverse effects has been small (typically 10-36%). It cannot be assumed that the effects of omega-3 fatty acids are the same in patients with diabetes mellitus as in nondiabetic subjects or patients with primary hyperlipidemia. First, the biosynthesis and composition of fatty acids is abnormal in diabetic animals and possibly in diabetic patients. Second, many potential mechanisms implicated in the pathogenesis of atherosclerosis are present in diabetic but not necessarily in nondiabetic subjects. Third, the mechanisms of many of the risk factors in diabetic patients differ from the mechanisms of these abnormalities in nondiabetic subjects, reflecting the effects of insulin deficiency, hyperglycemia, and their sequelae. Finally, because diabetes is a heterogeneous group of diseases, the effects of omega-3 fatty acids must be addressed separately for patients with insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, and possibly other forms of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased insulin-like growth factor II production and consequent suppression of growth hormone secretion: a dual mechanism for tumor-induced hypoglycemia.

We investigated the pathophysiology of fasting hypoglycemia associated with large tumors of mesenchymal origin. We studied two patients with symptomatic fasting hypoglycemia (plasma glucose, 1.92 and 2.03 mmol/L) and a large mesenchymal neoplasm. Before therapy, the plasma insulin-like growth factor II (IGF-II) level measured by RIA was elevated (1879 and 1084 micrograms/L; normal range, 358-854 micrograms/L), the serum GH response to hypoglycemia was impaired, and the plasma IGF-I level was low in both patients. After treatment of the tumor, all of these abnormalities resolved in both patients. Northern blot analysis of tumor RNA revealed extremely high levels of IGF-II mRNA (greater than 100-fold higher than those in normal adult liver). Tumor fragments released IGF-II into tissue culture medium (2.1 and 7.2 micrograms IGF-II/g tissue.24 h). These findings indicate that secretion of IGF-II into the circulation by the tumor was the likely source of the elevated plasma IGF-II levels. We suggest that the primary event in tumor-induced hypoglycemia is overproduction of IGF-II by the tumor, which gives rise to hypoglycemia by a dual mechanism: increased glucose utilization mediated by the insulin-like actions of IGF-II and inhibition of GH secretion.