Further studies on the antinociceptive effects ofΔ acid

The antinociceptive effects of (THC-7-oic) acid have been investigated further with particular regard to the influence of certain experimental parameters in the hot plate test. These included the degree of the thermal stimulus, the nature of the vehicle and a possible role for copper in the response. A temperature effect similar to that seen with nonsteroidalantiinflammatory drugs (NSAIDs) was observed, 55° produced observable antinociception, however, at a surface temperature of 58°C no drug effect was seen. Non-aqeous vehicles such as peanut oil increased the potency of THC-7-oic acid. Finally, the substitution of purified water for tap water reduced,the drug response which could be partially restored by adding copper to the purified drinking water. An increase in the inhibitory effect when copper was added was also seenin vitro in a cell culture model where the acid reduced prostaglandin synthesis induced by THC. Our findings suggest that THC-7-oic acid probably acts by mechanisms similar to the NSAIDs and that the above mentioned experimental conditions can greatly influence the outcome of studies with this agent.     

Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties

1. 15-Lipoxygenase (15-LO) has been implicated in the pathogenesis of atherosclerosis because of its localization in lesions and the many biological activities exhibited by its products. To provide further evidence for a role of 15-LO, the effects of PD 146176 on the development of atherosclerosis in cholesterol-fed rabbits were assessed. This novel drug is a specific inhibitor of the enzyme in vitro and lacks significant non specific antioxidant properties.
2. PD 146176 inhibited rabbit reticulocyte 15-LO through a mixed noncompetitive mode with a K_i of 197 nM. The drug had minimal effects on either copper or 2,2′-azobis(2-amidinopropane)hydrochloride (ABAP) induced oxidation of LDL except at concentrations 2 orders higher than the K_i.
3. Control New Zealand rabbits were fed a high-fat diet containing 0.25% wt./wt. cholesterol; treated animals received inhibitor in this diet (175 mg kg⁻¹, b.i.d.). Plasma concentrations of inhibitor were similar to the estimated K_i (197 nM). During the 12 week study, there were no significant differences in weight gain, haematocrit, plasma total cholesterol concentrations, or distribution of lipoprotein cholesterol.
4. The drug plasma concentrations achieved in vivo did not inhibit low-density lipoprotein (LDL) oxidation in vitro. Furthermore, LDL isolated from PD 146176-treated animals was as susceptible as that from controls to oxidation ex vivo by either copper or ABAP.
5. PD 146176 was very effective in suppressing atherogenesis, especially in the aortic arch where lesion coverage diminished from 15±4 to 0% (P<0.02); esterified cholesterol content was reduced from 2.1±0.7 to 0 μg mg⁻¹ (P<0.02) in this region. Immunostainable lipid-laden macrophages present in aortic intima of control animals were totally absent in the drug-treated group.
6. Results of these studies are consistent with a role for 15-LO in atherogenesis.

     

Photothermal effects of laser tissue soldering

Low-strength anastomoses and thermal damage of tissue are major concerns in laser tissue welding techniques where laser energy is used to induce thermal changes in the molecular structure of the tissues being joined, hence allowing them to bond together. Laser tissue soldering, on the other hand, is a bonding technique in which a protein solder is applied to the tissue surfaces to be joined, and laser energy is used to bond the solder to the tissue surfaces. The addition of protein solders to augment tissue repair procedures significantly reduces the problems of low strength and thermal damage associated with laser tissue welding techniques. Investigations were conducted to determine optimal solder and laser parameters for tissue repair in terms of tensile strength, temperature rise and damage and the microscopic nature of the bonds formed. An in vitro study was performed using an 808 nm diode laser in conjunction with indocyanine green (ICG)-doped albumin protein solders to repair bovine aorta specimens. Liquid and solid protein solders prepared from 25% and 60% bovine serum albumin (BSA), respectively, were compared. The efficacy of temperature feedback control in enhancing the soldering process was also investigated. Increasing the BSA concentration from 25% to 60% greatly increased the tensile strength of the repairs. A reduction in dye concentration from 2.5 mg ml(-1) to 0.25 mg ml(-1) was also found to result in an increase in tensile strength. Increasing the laser irradiance and thus surface temperature resulted in an increased severity of histological injury. Thermal denaturation of tissue collagen and necrosis of the intimal layer smooth muscle cells increased laterally and in depth with higher temperatures. The strongest repairs were produced with an irradiance of 6.4 W cm(-2) using a solid protein solder composed of 60% BSA and 0.25 mg ml(-1) ICG. Using this combination of laser and solder parameters, surface temperatures were observed to reach 85+/-5 degrees C with a maximum temperature difference through the 150 microm thick solder strips of about 15 degrees C. Histological examination of the repairs formed using these parameters showed negligible evidence of collateral thermal damage to the underlying tissue. Scanning electron microscopy suggested albumin intertwining within the tissue collagen matrix and subsequent fusion with the collagen as the mechanism for laser tissue soldering. The laser tissue soldering technique is shown to be an effective method for producing repairs with improved tensile strength and minimal collateral thermal damage over conventional laser tissue welding techniques.     

Comparative breast tumor imaging and comparative in vitro metabolism of 16alpha-[18F]fluoroestradiol-17beta and 16beta-[18F]fluoromoxestrol in isolated hepatocytes

16beta-[18F]Fluoromoxestrol ([18]betaFMOX) is an analog of 16alpha-[18F]fluoroestradiol-17beta ([18F]FES), a radiopharmaceutical known to be an effective positron emission tomography (PET) imaging agent for estrogen receptor-positive (ER+) human breast tumors. Based on comparisons of target tissue uptake efficiency and selectivity in a rat model, [18F]betaFMOX was predicted to be as effective an imaging agent as [18F]FES. However, in a preliminary PET imaging study with [18F]FMOX of 12 patients, 3 of whom had ER+ breast cancer, no tumor localization of [18F]betaFMOX was observed. In search for an explanation for the unsuccessful [18F]betaFMOX clinical trial, we have examined the rate of metabolism of [18F]FMOX and [18F]FES in isolated rat, baboon, and human hepatocytes. We have also studied the effect of the serum protein sex hormone-binding globulin (SHBG), which binds [18F]FES better than [18F]betaFMOX, on these rates of metabolism. Immature rat hepatocytes were found to metabolize [18F]FES 31 times faster than [18F]betaFMOX, whereas mature rat cells metabolized [18F]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [18F]betaFMOX. In the presence of SHBG, the metabolic consumption rate for [18F]FES in mature rat hepatocytes decreased by 26%. Thus, the very favorable target tissue uptake characteristics of [18F]betaFMOX determined in the rat probably result from its comparative resistance to metabolism (vis-a-vis [18F]FES) in this species, an advantage that is strongly reflected in comparative metabolism rates in rat hepatocytes. In the baboon and human, [18F]FES is extensively protein bound and protected from metabolism, an effect that may be reflected to a degree as a decrease in the rate of metabolism of this compound in baboon and human hepatocytes relative to [18F]betaFMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake of [18F]FES in ER+ tumors by selectively protecting this ligand from metabolism and ensuring its delivery to receptor-containing cells. In addition to current screening methods for 18F-estrogens that involve evaluating in vivo ER-mediated uptake in the immature female rat, studies comparing the metabolism of the new receptor ligands in isolated hepatocytes, especially those from primates or humans, may assist in predicting the potential of these ligands for human PET imaging.     

Simultaneous irradiation and imaging of blood vessels during pulsed laser delivery

BACKGROUND AND OBJECTIVE: Simultaneous irradiation and viewing of 10-120 microm cutaneous blood vessels were performed to investigate the effects of 2-micros 577-nm dye laser pulses. STUDY DESIGN/MATERIALS AND METHODS: A modified scanning laser confocal microscope recorded vessel response to different radiant exposures (J/cm2). Probit analysis determined the 50% probability ("threshold") radiant exposure necessary to cause embolized or partly occluding coagula, coagula causing complete blood flow stoppage, and hemorrhage. RESULTS: A statistically significant difference in the threshold radiant exposure existed for each damage category for blood vessels 10-30 microm in diameter, but not for larger vessels. For vessels over 60 microm, complete flow stoppage was unattainable; increasing laser pulse energy produced hemorrhage. In larger vessels, coagula often were attached to the superficial vessel wall while blood flowed underneath. Monte Carlo optical and finite difference thermal modeling confirmed experimental results. CONCLUSION: These results provide insight into the role of pulse duration and vessel diameter in the outcome of pulsed dye laser irradiation.     

Chronic symptoms in construction workers treated for musculoskeletal injuries.

BACKGROUND: Soft tissue musculoskeletal injuries make up a high proportion of all work-related injuries in construction. Data from Workers' Compensation claims indicate that strains and sprains are the leading compensable injury for construction workers. This study describes the consequences of soft tissue musculoskeletal injuries for construction workers, and assesses the persistence of symptoms after an injury and the impact of that injury on return to work. METHODS: Through an Emergency Department surveillance system [Hunting et al., 1994a], we recorded 176 construction worker visits, from 5/01/93 through 2/28/95, for strains, sprains, joint injury or pain, tendinitis, dislocations, hernias, or other musculoskeletal injuries excluding fractures. Telephone interviews were conducted several months after workers had visited the emergency room for a musculoskeletal injury. RESULTS: Seventy individuals were interviewed about the long-term impacts of 72 incidents that had resulted in work-related musculoskeletal injuries. For 46 (62%) of the 74 diagnoses, problems continued beyond two months. The likelihood of problems continuing more than two months varied considerably by body location of injury. Hispanic workers and older workers were more likely to have continuing symptoms. Eleven of the 45 construction workers with symptoms persisting longer than two months were not employed at the time of the interview. Only 11 of the 45 workers with ongoing symptoms told us that modifications had been made to their jobs to accommodate their symptoms. About one-quarter of these 45 subjects reported substantial effects on home or work life. CONCLUSIONS: Acute musculoskeletal injuries in construction workers frequently result in chronic symptoms, and those with chronic symptoms report substantial effects of the injury on their quality of life. Job accommodations were made in a minority of these injuries. These findings point to the need for heightened efforts for injury prevention in this industry.     

Women's perceptions of breast cancer risk: how you ask matters.

BACKGROUND: Some studies suggest that women dramatically overestimate the risk of having breast cancer while others conclude that they underestimate it. To understand better how women perceive the chance of getting breast cancer, the authors asked women to estimate the risk in several ways. Each woman's answer was related to her actual risk. METHODS: Women were randomly selected from a registry of female veterans in New England. A mailed questionnaire asked each woman to estimate her ten-year risk of dying from breast cancer as a number out of 1,000 ("___ in 1,000" perceived risk) and whether this risk was higher than, the same as, or lower than that of an average woman her age (comparative perceived risk). The woman was also asked to compare her risk of dying from breast cancer with her risk of dying from heart disease. Risk-factor data were collected so that each woman's actual risk of breast cancer death could be estimated (actual risk). RESULTS: 201 women had complete data. The median age of the respondents was 62 years (range 27-80), and 98% were high school graduates. Most women (98%) overestimated the "___ in 1,000" risk of breast cancer death-half by eightfold or more (interquartile range, 4-36-fold overestimates). In contrast, only 10% of these women thought that they were at higher risk than an average woman their age. Most correctly thought that their risk of dying from breast cancer was lower than their risk of dying from heart disease. The women's "____in 1,000" perceived risks of breast cancer death were unrelated to their actual risks and had no significant agreement with an external bench-mark of importantly "high risk" (i.e., met risk criteria for the Tamoxifen primary prevention trial). In contrast, the women's comparative perceptions of being at low, average or high risk were related to actual risks and significantly agreed with the "high risk" benchmark. Most women not at importantly "high risk" correctly classified themselves; however, almost two thirds of "high risk" women misclassified themselves as "average or lower than average risk." CONCLUSIONS: The method used to elicit perceptions of risk matters. These women's responses to the comparative questions showed that they "knew more" about their actual risks than their open-ended numeric responses suggested.