Sun-related knowledge and practices in Irish construction and agricultural workers.

BACKGROUND: Agricultural and construction workers spend much of their work time outdoors and have higher risks of developing skin cancer when compared to indoor workers. However, there is limited research on ultraviolet radiation (UVR) exposure knowledge, sun safety practices and constraints within these occupational groups in Ireland. AIMS: This study aimed to examine self-reported time spent outdoors in a sample of Irish agricultural and construction workers; to describe and compare UVR exposure knowledge, safety practices and perceived constraints in both occupational groups, and to assess the association of demographic, personal and occupational factors with sun-related knowledge, practices and perceived constraints. METHODS: Agricultural workers (n = 154) and construction workers (n = 467) completed a questionnaire, which measured solar UVR exposure knowledge, safety practices, and perceived constraints to sun personal protective equipment and sunscreen use in addition to demographic, personal, and workplace characteristics. Mann-Whitney and Kruskal-Wallis tests were used to examine differences in knowledge, practices and perceived constraints by these characteristics. RESULTS: Both groups spend a significant proportion of their working week outdoors (25 hours per week on average). Although participation in sun safety training was high for both groups, UVR exposure knowledge and sunscreen use were low, and annual rates of reported sunburn were high. Knowledge, practices and perceived constraints also differed significantly according to demographic, personal, occupational and workplace characteristics. CONCLUSIONS: In addition to training by employers and advisory groups, interventions are required to address perceived barriers that impede the uptake and usage of control measures that can lower risk.

Contribution of solid fuel, gas combustion, or tobacco smoke to indoor air pollutant concentrations in Irish and Scottish homes.

UNLABELLED: There are limited data describing pollutant levels inside homes that burn solid fuel within developed country settings with most studies describing test conditions or the effect of interventions. This study recruited homes in Ireland and Scotland where open combustion processes take place. Open combustion was classified as coal, peat, or wood fuel burning, use of a gas cooker or stove, or where there is at least one resident smoker. Twenty-four-hour data on airborne concentrations of particulate matter<2.5 µm in size (PM2.5), carbon monoxide (CO), endotoxin in inhalable dust and carbon dioxide (CO2), together with 2-3 week averaged concentrations of nitrogen dioxide (NO2) were collected in 100 houses during the winter and spring of 2009-2010. The geometric mean of the 24-h time-weighted-average (TWA) PM2.5 concentration was highest in homes with resident smokers (99 µg/m3--much higher than the WHO 24-h guidance value of 25 µg/m3). Lower geometric mean 24-h TWA levels were found in homes that burned coal (7 µg/m3) or wood (6 µg/m3) and in homes with gas cookers (7 µg/m3). In peat-burning homes, the average 24-h PM2.5 level recorded was 11 µg/m3. Airborne endotoxin, CO, CO2, and NO2 concentrations were generally within indoor air quality guidance levels. PRACTICAL IMPLICATIONS: Little is known about indoor air quality (IAQ) in homes that burn solid or fossil-derived fuels in economically developed countries. Recent legislative changes have moved to improve IAQ at work and in enclosed public places, but there remains a real need to begin the process of quantifying the health burden that arises from indoor air pollution within domestic environments. This study demonstrates that homes in Scotland and Ireland that burn solid fuels or gas for heating and cooking have concentrations of air pollutants generally within guideline levels. Homes where combustion of cigarettes takes place have much poorer air quality.

Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha.

Regulation of NF-kappaB occurs through phosphorylation-dependent ubiquitination of IkappaBalpha, which is degraded by the 26S proteasome. Recent studies have shown that ubiquitination of IkappaBalpha is carried out by a ubiquitin-ligase enzyme complex called SCF(beta(TrCP)). Here we show that Nedd8 modification of the Cul-1 component of SCF(beta(TrCP)) is important for function of SCF(beta(TrCP)) in ubiquitination of IkappaBalpha. In cells, Nedd8-conjugated Cul-1 was complexed with two substrates of SCF(beta(TrCP)), phosphorylated IkappaBalpha and beta-catenin, indicating that Nedd8-Cul-1 conjugates are part of SCF(beta(TrCP)) in vivo. Although only a minute fraction of total cellular Cul-1 is modified by Nedd8, the Cul-1 associated with ectopically expressed betaTrCP was highly enriched for the Nedd8-conjugated form. Moreover, optimal ubiquitination of IkappaBalpha required Nedd8 and the Nedd8-conjugating enzyme, Ubc12. The site of Nedd8 ligation to Cul-1 is essential, as SCF(beta(TrCP)) containing a K720R mutant of Cul-1 only weakly supported IkappaBalpha ubiquitination compared to SCF(beta(TrCP)) containing WT Cul-1, suggesting that the Nedd8 ligation of Cul-1 affects the ubiquitination activity of SCF(beta(TrCP)). These observations provide a functional link between the highly related ubiquitin and Nedd8 pathways of protein modification and show how they operate together to selectively target the signal-dependent degradation of IkappaBalpha.

Noninvasive quantification of coronary blood flow reserve in humans using myocardial contrast echocardiography.

BACKGROUND: We hypothesized that coronary blood flow (CBF) reserve could be quantified noninvasively in humans using myocardial contrast echocardiography (MCE). METHODS AND RESULTS: Eleven patients with normal epicardial coronary arteries (group I) and 19 with single-vessel coronary stenosis (group II) underwent quantitative coronary angiography, MCE, and CBF velocity measurements at rest and during intravenous adenosine infusion. In group I patients, MCE-derived myocardial blood flow (MBF) velocity reserve (2.4+/-0.08) was similar to CBF velocity reserve using a Doppler flow wire (2.4+/-1.1). Patients with a single risk factor had a significantly higher MBF reserve (3.0+/-0.89) than those with >/=2 risk factors (1.7+/-0.22). In group II patients, significant differences were found in MBF velocity reserve in patients with mild (<50%), moderate (50% to 75%), or severe (>75%) stenoses (2.2+/-0.40, 1.6+/-0.65, and 0.55+/-0.19, respectively; P=0.005). A linear relation was found between flow velocity reserve determined using the 2 methods (r=0.76, P<0.001), and a curvilinear relation was noted between the percent coronary stenosis measured using quantitative coronary angiography and velocity reserve using both methods. CONCLUSIONS: CBF reserve can be measured in humans using MCE. This method may allow the noninvasive assessment of coronary stenosis severity and the detection of microvascular dysfunction.

Microbubble persistence in the microcirculation during ischemia/reperfusion and inflammation is caused by integrin- and complement-mediated adherence to activated leukocytes.

BACKGROUND: Albumin microbubbles that are used for contrast echocardiography persist within the myocardial microcirculation after ischemia/reperfusion (I-R). The mechanism responsible for this phenomenon is unknown. METHODS AND RESULTS: Intravital microscopy of the microcirculation of exteriorized cremaster muscle was performed in 12 wild-type mice during intravenous injections of fluorescein-labeled microbubbles composed of albumin, anionic lipids, or cationic lipids. Injections were performed at baseline and after 30 to 90 minutes of I-R in 8 mice and 2 hours after intrascrotal tumor necrosis factor-alpha (TNF-alpha) in 4 mice. Microbubble adherence at baseline was uncommon (<2/50 high-power fields). After I-R, adherence increased (P<0.05) to 9+/-5 and 5+/-4 per 50 high-power fields for albumin and anionic lipid microbubbles, respectively, due to their attachment to leukocytes adherent to the venular endothelium. TNF-alpha produced even greater microbubble binding, regardless of the microbubble shell composition. The degree of microbubble attachment correlated (r=0.84 to 0.91) with the number of adhered leukocytes. Flow cytometry revealed that microbubbles preferentially attached to activated leukocytes. Albumin microbubble attachment was inhibited by blocking the leukocyte beta(2)-integrin Mac-1, whereas lipid microbubble binding was inhibited when incubations were performed in complement-depleted or heat-inactivated serum rather than control serum. CONCLUSIONS: Microvascular attachment of albumin and lipid microbubbles in the setting of I-R and TNF-alpha-induced inflammation is due to their beta(2)-integrin- and complement-mediated binding to activated leukocytes adherent to the venular wall. Thus, microbubble persistence on contrast ultrasonography may be useful for the detection and monitoring of leukocyte adhesion in inflammatory diseases.

Noninvasive imaging of inflammation by ultrasound detection of phagocytosed microbubbles.

BACKGROUND: We have previously shown that microbubbles adhere to leukocytes in regions of inflammation. We hypothesized that these microbubbles are phagocytosed by neutrophils and monocytes and remain acoustically active, permitting their detection in inflamed tissue. METHODS AND RESULTS: In vitro studies were performed in which activated leukocytes were incubated with albumin or lipid microbubbles and observed under microscopy. Microbubbles attached to the surface of activated neutrophils and monocytes, were phagocytosed, and remained intact for up to 30 minutes. The rate of destruction of the phagocytosed microbubbles on exposure to ultrasound was less (P

Noninvasive prediction of ultimate infarct size at the time of acute coronary occlusion based on the extent and magnitude of collateral-derived myocardial blood flow.

BACKGROUND: We hypothesized that by detecting regions with adequate collateral-derived myocardial blood flow (MBF) within the risk area (RA), we could predict ultimate infarct size (IS) at the time of coronary occlusion. METHODS AND RESULTS: Group 1 dogs (n=15) underwent coronary occlusion without reperfusion, whereas group 2 dogs (n=6) underwent both occlusion and reperfusion. RA was measured with aortic root injections of microbubbles. Myocardial contrast echocardiography (MCE) was performed with high mechanical index intermittent harmonic imaging at pulsing intervals (PIs) of <1 to 30 cardiac cycles during an intravenous infusion of microbubbles (Sonozoid). MBF was measured with radiolabeled microspheres, and postmortem tissue staining was used to determine IS. Perfusion defect size (PDS) on MCE varied with the PI and was largest at a PI of 2.6+/-0.4 seconds, where it correlated well with RA (r=0.82). PDS was smallest at a PI of >/=10.6+/-1.5 seconds, where it correlated closely with IS (r>/=0.92). Areas that underwent necrosis could be identified early after coronary occlusion as having the lowest microvascular flow velocity (beta) and MCE-derived MBF (Axbeta). The results were similar with or without reperfusion. Because of variability in collateral-derived MBF, there was no correlation between RA and ultimate IS (P=0.37). The extent of regional dysfunction also correlated poorly with IS (r=0.31). CONCLUSIONS: MCE can be used immediately after coronary occlusion to define ultimate IS by measuring the magnitude and spatial extent of collateral-derived residual MBF within the RA. Thus, it could help individualize risk and management in acute myocardial infarction.

Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment.

Despite intensive study, the relation between insulin's action on blood flow and glucose metabolism remains unclear. Insulin-induced changes in microvascular perfusion, independent from effects on total blood flow, could be an important variable contributing to insulin's metabolic action. We hypothesized that modest, physiologic increments in plasma insulin concentration alter microvascular perfusion in human skeletal muscle and that these changes can be assessed using contrast-enhanced ultrasound (CEU), a validated method for quantifying flow by measurement of microvascular blood volume (MBV) and microvascular flow velocity (MFV). In the first protocol, 10 healthy, fasting adults received insulin (0.05 mU. kg(-1). min(-1)) via a brachial artery for 4 h under euglycemic conditions. At baseline and after insulin infusion, MBV and MFV were measured by CEU during continuous intravenous infusion of albumin microbubbles with intermittent harmonic ultrasound imaging of the forearm deep flexor muscles. In the second protocol, 17 healthy, fasting adults received a 4-h infusion of either insulin (0.1 mU. kg(-1). min(-1), n = 9) or saline (n = 8) via a brachial artery. Microvascular volume was assessed in these subjects by an alternate CEU technique using an intra-arterial bolus injection of albumin microbubbles at baseline and after the 4-h infusion. With both protocols, muscle glucose uptake, plasma insulin concentration, and total blood flow to the forearm were measured at each stage. In protocol 2 subjects, tissue extraction of 1-methylxanthine (1-MX) was measured as an index of perfused capillary volume. Caffeine, which produces 1-MX as a metabolite, was administered to these subjects before the study to raise plasma 1-MX levels. In protocol 1 subjects, insulin increased muscle glucose uptake (180%, P < 0.05) and MBV (54%, P < 0.01) and decreased MFV (-42%, P = 0.07) in the absence of significant changes in total forearm blood flow. In protocol 2 subjects, insulin increased glucose uptake (220%, P < 0.01) and microvascular volume (45%, P < 0.05) with an associated moderate increase in total forearm blood flow (P < 0.05). Using forearm 1-MX extraction, we observed a trend, though not significant, toward increasing capillary volume in the insulin-treated subjects. In conclusion, modest physiologic increments in plasma insulin concentration increased microvascular blood volume, indicating altered microvascular perfusion consistent with a mechanism of capillary recruitment. The increases in microvascular (capillary) volume (despite unchanged total blood flow) indicate that the relation between insulin's vascular and metabolic actions cannot be fully understood using measurements of bulk blood flow alone.

Quantification of renal blood flow with contrast-enhanced ultrasound.

OBJECTIVES: The goal of this study was to determine the ability of contrast-enhanced ultrasound (CEU) to quantify renal tissue perfusion. BACKGROUND: The kinetics of tracers used to assess renal perfusion are often complicated by countercurrent exchange, tubular transport or glomerular filtration. We hypothesized that, because gas-filled microbubbles are pure intravascular tracers with a rheology similar to that of red blood cells, CEU could be used to quantify renal tissue perfusion. METHODS: During a continuous venous infusion of microbubbles (SonoVue), regional renal perfusion was quantified in nine dogs using CEU by destroying microbubbles and measuring their tissue replenishment with intermittent harmonic imaging. Both renal blood volume fraction and microbubble velocity were derived from pulsing-interval versus video-intensity plots. The product of the two was used to calculate renal nutrient blood flow. Renal arterial blood flow was independently measured with ultrasonic flow probes placed directly on the renal artery and was increased using dopamine and decreased by placement of a renal artery stenosis. RESULTS: An excellent correlation was found between cortical nutrient blood flow using microbubbles and ultrasonic flow probe-derived renal blood flow (r = 0.82, p < 0.001) over a wide range (2.5 fold) of flows. CONCLUSIONS: Ultrasound examination during microbubble infusion can be used to quantify total organ as well as regional nutrient blood flow to the kidney.

Mental health clinicians' attitudes about reporting threats against the president.

OBJECTIVE: A recent review by the United States Secret Service of cases involving threats against the President indicated that about 50 percent of subjects had received mental health care. However, only 12 percent of referrals for investigation came from mental health professionals. This study explored reasons for this discrepancy by examining mental health clinicians' attitudes about reporting threats against the President to the Secret Service. METHODS: A questionnaire developed using findings from a series of focus groups was mailed to a stratified sample of 1,200 psychiatrists, psychologists, and social workers in four states. The instrument included questions about their experience with threats against the President, factors that influence reporting of threats, and knowledge about the Secret Service and its functions. RESULTS: A total of 592 questionnaires were returned, for a response rate of 49.3 percent. Therapists know very little about the Secret Service and are unclear about how to appropriately respond to threats against the President by their clients. The majority of respondents (89.9 percent) indicated they would report a threat against the President only if they thought the threat was "real," contingent on situational and patient variables and elements of the threat itself. Most of the respondents (62.4 percent) indicated that regardless of what information they considered clinically relevant to the investigation. CONCLUSIONS: Given the importance of clinical information for assessing risk to the President, the Secret Service should consider increased educational efforts to inform the mental health community about the functions and mission of the Secret Service and to clarify professional obligations to report threats against the President.

Osteomyelitis caused by Enterobacter taylorae, formerly enteric group 19.

The first case of osteomyelitis caused by Enterobacter taylorae is presented. The infection occurred as a complication to an open fracture in an otherwise healthy host. Despite antimicrobial therapy, based on in vitro susceptibilities, it was not possible to establish a microbiologic cure.

Mental health consultant to law enforcement: Secret Service development of a Mental Health Liaison Program.

The Mental Health Liaison Program developed and used by the Secret Service is presented as a model for comprehensive, multidimensional interactions between law enforcement and mental health systems, with particular focus on assessing and preventing violent behavior. The structure of the program pairs consultants--psychologists and psychiatrists--with Secret Service field offices to provide (a) consultation regarding risk assessment and case management of individuals who threaten or display inappropriate interest in the President or other protectees; (b) training for agents on risk assessment, mental illness, and mental health care issues; and (c) liaison activities between the Secret Service and the mental health community. Practical benefits to the Secret Service are discussed to encourage more systematic use of broad based psychological and psychiatric consultation to law enforcement, with a goal of enhanced intersystem communication and collaboration. The need for program evaluation and outcome research is discussed in the context of applying the model to improve other mental health and law enforcement systems interactions.

Role of capillaries in determining CBF reserve: new insights using myocardial contrast echocardiography.

To define the role of capillaries in the control of coronary blood flow (CBF) reserve, we developed a model of the coronary circulation and evaluated experimental data in its context. Our model comprised three compartments connected in series (arterial, capillary, and venous), each with its own resistance. The resistance in each vascular compartment was derived from the model based on hemodynamic data obtained in nine dogs during baseline and stenosis, both at rest and during hyperemia. The capillary hydrostatic pressure was assumed to be constant in all stages. Although in the absence of stenosis, the contribution of capillaries to total myocardial vascular resistance was only 25 +/- 5% at rest, it increased to 75 +/- 14% during hyperemia, despite the total myocardial vascular resistance decreasing by 51 +/- 13%. In the presence of a noncritical stenosis, total myocardial vascular resistance decreased by 22 +/- 10% at rest, with no change in capillary resistance. During hyperemia, total myocardial vascular resistance increased by 58 +/- 50% in the presence of the noncritical stenosis. In this situation, because arteriolar and venular resistances were already minimal, the increase in myocardial vascular resistance was due to increased capillary resistance, making it the predominant source (84 +/- 8%) of total myocardial vascular resistance. Myocardial video intensity (VI) on myocardial contrast echocardiography (MCE), which reflects capillary blood volume, decreased distal to the stenosis during hyperemia. In the presence of a flow-limiting stenosis at rest, myocardial VI also decreased, indicating that decrease in CBF was associated with an increase in capillary resistance. Our findings also provide an alternative explanation for the critical coronary closing pressure. Thus, contrary to previously held notions, capillaries play a vital role in the regulation of CBF.

Mechanism of reversible (99m)Tc-sestamibi perfusion defects during pharmacologically induced vasodilatation.

Reversible perfusion defects on (99m)Tc-sestamibi imaging during hyperemia are thought to occur due to myocardial blood flow (MBF) "mismatch" between regions with and without stenosis. We have recently shown that myocardial blood volume (MBV) distal to a stenosis decreases during hyperemia, resulting in a reversible perfusion defect on myocardial contrast echocardiography (MCE). In this study, we hypothesized that a reversible perfusion defect on (99m)Tc-sestamibi imaging during hyperemia results from the same mechanism. We tested our hypothesis under the following conditions: 1) increases in MBF in the absence of changes in MBV by using direct intracoronary infusion of adenosine (group I, n = 10 dogs); 2) decrease in MBV despite an increase in MBF by left main infusion of adenosine proximal to a noncritical coronary stenosis placed on either coronary artery (group II, n = 13 dogs); and 3) reduction in both resting MBF and MBV by placement of a severe stenosis (group III, n = 7 dogs). In group I dogs, no difference in MBV or (99m)Tc-sestamibi uptake was found between the two coronary beds despite an up to fourfold increase in MBF in one bed with adenosine. In group II dogs, MBV distal to the stenosis decreased during hyperemia despite a twofold increase in mean MBF. A good correlation was found between (99m)Tc-sestamibi uptake and MBV ratios from the stenosed versus normal bed (r = 0.91, P < 0.001). In group III dogs, both MBF and MBV were decreased in the stenosed bed at rest with a good correlation noted between (99m)Tc-sestamibi uptake and MBV ratios from the stenosed versus normal bed (r = 0.92, P = 0.004). We conclude that reversible defects on (99m)Tc-sestamibi during vasodilator stress imaging are related to decreases in MBV distal to a stenosis and not to "flow mismatch" between beds. The decrease in MBV results in reduced (99m)Tc-sestamibi uptake during hyperemia.

Relation between regional function and coronary blood flow reserve in multivessel coronary artery stenosis.

In the setting of chronic coronary stenoses, percent wall thickening (%WT) both at rest and during catecholamine stimulation can be abnormal despite normal resting myocardial blood flow (MBF). We hypothesized that this phenomenon is related to abnormal MBF reserve. Accordingly, 15 dogs were studied between 7 and 10 days after placement of Ameroid constrictors around the proximal coronary arteries and their major branches, at a time when collateral development had not yet occurred. %WT and MBF were measured at rest, after 0.56 mg/kg of dipyridamole, and at incremental doses of dobutamine (5-40 microgram. kg(-1). min(-1)). Resting %WT and MBF were normal in all four sham dogs. Resting transmural MBF was normal in all segments in the 11 study dogs, despite reduced (-2 SD of normal) %WT (<30%) in 40 of 82 segments. MBF reserve was reduced (<3) in segments with reduced %WT, and a close coupling was noted between resting %WT and MBF reserve. All segments showed an increase in %WT with dobutamine up to a dose of 20 microgram. kg(-1). min(-1), above which those with abnormal endocardial MBF reserve showed a "biphasic" response. It is concluded that, in the presence of chronic coronary stenoses, abnormalities in resting %WT as well as inducible reduction in %WT during pharmacological stress are related to the degree of abnormal MBF reserve.

Changes in myocardial blood volume over a wide range of coronary driving pressures: role of capillaries beyond the autoregulatory range.

OBJECTIVE: To determine whether, when the vasomotor capacity of the coronary arterioles is exhausted at rest, myocardial blood volume decreases in order to maintain a normal capillary hydrostatic pressure, even at the expense of myocardial oxygen delivery. METHODS: 18 dogs were studied. In group 1 (n = 9), coronary driving pressure (CDP) was reduced by 10-80 mm Hg below normal by a stenosis; in group 2 (n = 9), it was increased 20-80 mm Hg above baseline by increasing aortic pressure with phenylephrine. Myocardial contrast echocardiography (MCE) was undertaken to measure the myocardial blood volume fraction and myocardial blood flow (MBF). RESULTS: In group 1 dogs, as CDP was reduced, both coronary blood flow (CBF) and MBF decreased. Myocardial blood volume fraction also decreased and myocardial vascular resistance increased, while coronary sinus PO2 decreased. In group 2 dogs, as CDP was increased, epicardial CBF increased but MBF remained unchanged because of a decrease in myocardial blood volume fraction. Myocardial vascular resistance decreased, however, implying the presence of coronary arteriovenous shunting, which was supported by a progressive increase in the coronary sinus PO2. CONCLUSIONS: When arteriolar tone is exhausted so that CBF becomes dependent on CDP, myocardial blood volume decreases in order to maintain a constant capillary hydrostatic pressure, which takes precedence over myocardial oxygen delivery. These novel findings implicate capillaries in the regulation of CBF beyond the autoregulatory range.

A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination.

Temporal control of p27(Kip1) (p27) degradation imposes periodicity in its activity during cell cycle progression and its accumulation during cell cycle exit. Degradation of p27 is initiated by phosphorylation of p27 at Thr-187, which marks the protein for ubiquitination by SCF(Skp2) and subsequent proteolysis by the 26S proteasome. Here we show that the p27 ubiquitination activity in cell extracts depends on the presence of the ubiquitin-like protein Nedd8 and enzymes that catalyze Nedd8 conjugation to proteins. Moreover, we show that reconstitution of the p27 ubiquitination activity of recombinant SCF(Skp2) also requires Nedd8 conjugation pathway components. Inactivation of the Nedd8 conjugation pathway by a dominant negative mutant of the Nedd8-conjugating enzyme Nce1/Ubc12 blocks the ubiquitination and degradation of p27 in cell extracts. Consistent with a role in cell-cycle progression, Nedd8 is expressed in proliferating cells and is itself down-regulated upon cellular differentiation. These results suggest that the Nedd8 conjugation pathway may regulate the turnover of p27(Kip1), independently of p27 phosphorylation, and further establishes the identity of protein components involved in p27 ubiquitination. Finally, these findings provide a direct demonstration of a function for Nedd8 in a biological process.

A new model of cancer cachexia: contribution of the ubiquitin-proteasome pathway.

A new model of cachexia is described in which muscle protein metabolism related to the ubiquitin-proteasome pathway was investigated. Cloning of the colon-26 tumor produced a cell line, termed R-1, which induced cytokine (noninterleukin-1beta, interleukin-6 and tumor necrosis factor-alpha)-independent cachexia. Implantation of R-1 cells in mice elicited significant (20-30%) weight loss and decreased blood glucose by 70%, and adipose tissue levels declined by 95% and muscle weights decreased by 20-25%. Food intake was unaffected. The decrease in muscle weight reflected a decline in insoluble, but not soluble, muscle protein that was associated with a significant increase in net protein degradation. The rate of ubiquitin conjugation of proteins was significantly elevated in muscles of cachectic mice. Furthermore, the proteasome inhibitor lactacystin blocked the increase in protein breakdown but had no significant effect on proteolysis. Several markers of the ubiquitin-proteasome pathway, E2(14k) mRNA and E2(14k) protein and ubiquitin-protein conjugates, were not elevated. Future investigations with this new model should gain further insights into the mechanisms of cachexia and provide a background to evaluate novel and more efficacious therapies.