Effects of fenofibrate on lipid parameters in obese rhesus monkeys.

Fenofibrate is a member of the fibrate class of hypolipidemic agents used clinically to treat hypertriglyceridemia and mixed hyperlipidemia. The fibrates were developed primarily on the basis of their cholesterol and triglyceride lowering in rodents. Fibrates have historically been ineffective at lowering triglycerides in experimentally-induced dyslipidemia in nonhuman primate models. The spontaneously obese rhesus monkey is a well-recognized animal model for the study of human obesity and type 2 diabetes, and many of these monkeys exhibit naturally occurring lipid abnormalities, including elevated triglycerides and low HDL cholesterol (HDL-C), similar to patients with type 2 diabetes. To explore whether the obese rhesus model was predictive of the lipid lowering effects of fibrates, we evaluated fenofibrate in six hypertriglyceridemic, hyperinsulinemic, nondiabetic animals in a 20-week, dose-escalating study. The study consisted of a 4-week baseline period, two treatment periods of 10 mg/kg twice daily (b.i.d) for 4 weeks and 30 mg/kg b.i.d. for 8 weeks, and a 4-week washout period. Fenofibrate (30 mg/kg b.i.d) decreased serum triglycerides 55% and LDL-C 27%, whereas HDL-C increased 35%. Apolipoproteins B-100 and C-III levels were also reduced 70% and 29%, respectively. Food intake, body weight, and plasma glucose were not affected throughout the study. Interestingly, plasma insulin levels decreased 40% during the 30 mg/kg treatment period, suggesting improvement in insulin sensitivity. These results support the use of obese rhesus monkey as an excellent animal model for studying the effects of novel hypolipidemic agents, particularly agents that impact serum triglycerides and HDL-C.

A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.

The discovery that peroxisome proliferator-activated receptor (PPAR)-gamma was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-gamma in the regulation of carbohydrate and lipid metabolism. Through the use of high-throughput biochemical assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-gamma, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated hemoglobin. Whole body insulin sensitivity, as determined by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concentrations showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion experiments, animals treated with the PPAR-gamma agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidinedione identified as a high-affinity ligand for human PPAR-gamma. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clinical efficacy when used as monotherapy in type 2 diabetic patients. In addition, the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.

The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction.

AIMS/HYPOTHESIS: Although retinoid X receptor (RXR) and peroxisome proliferator activated receptor-gamma (PPARgamma) agonists have antidiabetic effects in hyperinsulinaemic animals, little information exists on their effects after pancreatic beta-cell failure. Thus, we examined if RXR and PPARgamma agonists alter distinct metabolic pathways in animals suffering from impaired insulin secretion. METHODS: Adverse side effects and antidiabetic responses were measured in db/db mice treated from 14-16 weeks of age with the RXR agonist, LG100268, and/or the PPARgamma agonists, BRL49653 or GW1929. RESULTS: In animals treated with LG100268 or BRL49653, serum glucose, glycohaemoglobin and the cardiovascular risk factor, fibrinogen, decreased to the same extent. Both of these agonists were equally effective at increasing insulin accumulation in beta cells, although neither agent had an effect on serum insulin concentrations. In contrast, the RXR agonist was less effective than the PPARgamma agonists at lowering serum triglycerides and non-esterified fatty acids and increasing interscapular brown fat and body weight. Further, LG100268 increased serum alkaline phosphatase and liver mass, hepatic fat accumulation, lauric acid hydroxylase activity, catalase-immunostaining and peroxisomal number more than the PPARgamma agonists. Moreover, co-treatment with the RXR and PPARgamma agonists reduced glucose, triglycerides, non-esterified fatty acids and cholesterol more than either agent alone. CONCLUSION/INTERPRETATION: These data suggest 1) RXR and PPARgamma agonists decrease islet degeneration, cardiovascular risk and cachexia during later stages of diabetes, 2) RXR agonists are less effective than PPARgamma agonists at decreasing serum lipids and causing weight gain and 3) RXR agonists have a more pronounced effect on liver metabolism (e.g. peroxisome accumulation and hepatomegaly) than PPARgamma agonists.

Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone.

The estrogen receptor (ER) mixed agonists tamoxifen and raloxifene have been shown to protect against bone loss in ovariectomized rats. However, the mechanism by which these compounds manifest their activity in bone is unknown. We have used a series of in vitro screens to select for compounds that are mechanistically distinct from tamoxifen and raloxifene in an effort to define the properties of an ER modulator required for bone protection. Using this approach, we identified a novel high affinity ER antagonist, GW5638, which when assayed in vitro functions as an ER antagonist, inhibiting the agonist activity of estrogen, tamoxifen, and raloxifene and reversing the "inverse agonist" activity of the pure antiestrogen ICI182,780. Thus, GW5638 appears to function as an antagonist in these in vitro systems, although in a manner distinct from other known ER modulators. Predictably, therefore, GW5638 alone displays minimal uterotropic activity in ovariectomized rats, but will inhibit the agonist activity of estradiol in this environment. Unexpectedly, however, this compound functions as a full ER agonist in bone and the cardiovascular system. These data suggest that the mechanism by which ER operates in different cells is not identical, and that classical agonist activity is not required for the bone protective activity of ER modulators.

Spinal cord injury: a 25-year morbidity and mortality study.

The morbidity and mortality occurring during 25 years following spinal cord injury were analyzed. A cohort of 230 patients was selected from the Vietnam Head and Spinal Cord Injury Study Registry meeting the following criteria: (1) survival beyond triage (72 hours); (2) significant myelopathy; and (3) availability of medical records. The military and Veteran's Hospital medical records were compiled and reviewed. Additional death records were obtained from the Department of Veterans Affairs pension office. The major morbidity problems continue to be sepsis related to genitourinary and decubiti sequelae. Psychosocial maladjustment and substance abuse were prevalent and created heavy health care demand. The most frequent cause of death was sepsis. Suicide in the paraplegic group occurred at a rate exceeding by 10 times the frequency reported for uninjured peers. Survival after 5 years approached but never reached the rate established for uninjured peers.

Activation of the nuclear receptor peroxisome proliferator-activated receptor gamma promotes brown adipocyte differentiation.

Brown adipose tissue (BAT) functions in non-shivering and diet-induced thermogenesis via its capacity for uncoupled mitochondrial respiration. BAT dysfunction in rodents is associated with severe defects in energy homeostasis, resulting in obesity and hyperglycemia. Here, we report that the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), a prostaglandin-activated transcription factor recently implicated as a central regulator of white adipose tissue differentiation, also regulates brown adipocyte function. PPARgamma is abundantly expressed in both embryonic and adult BAT. Treatment of CD-1 rats with the PPARgamma-selective ligand BRL49653, an anti-diabetic drug of the thiazolidinedione class, results in marked increases in the mass of interscapular BAT. In vitro, BRL49653 induces the terminal differentiation of the brown preadipocyte cell line HIB-1B as judged by both changes in cell morphology and expression of uncoupling protein and other adipocyte-specific mRNAs. These data demonstrate that PPARgamma is a key regulatory factor in brown adipocytes and suggest that PPARgamma functions not only in the storage of excess energy in white adipose tissue but also in its dissipation in BAT.

Frontal lobe injuries, violence, and aggression: a report of the Vietnam Head Injury Study.

Knowledge stored in the human prefrontal cortex may exert control over more primitive behavioral reactions to environmental provocation. Therefore, following frontal lobe lesions, patients are more likely to use physical intimidation or verbal threats in potential or actual confrontational situations. To test this hypothesis, we examined the relationship between frontal lobe lesions and the presence of aggressive and violent behavior. Fifty-seven normal controls and 279 veterans, matched for age, education, and time in Vietnam, who had suffered penetrating head injuries during their service in Vietnam, were studied. Family observations and self-reports were collected using scales and questionnaires that assessed a range of aggressive and violent attitudes and behavior. Two Aggression/Violence Scale scores, based on observer ratings, were constructed. The results indicated that patients with frontal ventromedial lesions consistently demonstrated Aggression/Violence Scale scores significantly higher than controls and patients with lesions in other brain areas. Higher Aggression/Violence Scale scores were generally associated with verbal confrontations rather than physical assaults, which were less frequently reported. The presence of aggressive and violent behaviors was not associated with the total size of the lesion nor whether the patient had seizures, but was associated with a disruption of family activities. These findings support the hypothesis that ventromedial frontal lobe lesions increase the risk of aggressive and violent behavior.

Macroscopic evidence of the effect of interfacial slippage on adhesion.

The adhesion strengths of a viscoelastic adhesive were measured on various substrates that were prepared by grafting silanes bearing organic functional groups to silicon wafers. Conventional theories predict that adhesion should be proportional to the surface free energy of the substrate; but adhesion on a fluorocarbon surface was significantly greater than on some of the hydrocarbon surfaces, although the fluorocarbon surface has the lowest surface free energy. This result could be explained by invoking a model of adhesion based on the slippage of the adhesive at the interface.

In vivo antitumor activity of two new seven-substituted water-soluble camptothecin analogues.

The development of camptothecin-like compounds as inhibitors of topoisomerase I for the treatment of resistant tumors has generated clinical excitement in this new class of drugs. We have developed two novel water-soluble camptothecin analogues which are specific inhibitors of topoisomerase I and are potent cytotoxins with significant antitumor activity. We added water-solubilizing groups off position 7 in the B ring of either 10,11-ethylenedioxy- or 10,11-methylenedioxy-20(S)-camptothecin. These water-soluble camptothecin analogues were demonstrated to be nanamolar inhibitors of the topoisomerase I enzyme in the cleavable complex assay. The compounds, GI147211 [7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camp tot hecin], and GI149893 [7-(4-methylpiperazinomethylene)-10,11-methylenedioxy-20(S)-cam pto thecin], were compared to topotecan, a known water-soluble inhibitor of topoisomerase I. Both GI compounds were found to be slightly more potent than topotecan as inhibitors of topoisomerase I in the cleavable complex assay and were 1.5-2 times more soluble. Tumor cell cytotoxicity assays using 5 separate cell lines demonstrated that both GI compounds were 5-10 times more potent than topotecan, although by comparison all three topoisomerase I inhibitors were unaffected by the multidrug resistance P-glycoprotein. The antitumor activity of all three topoisomerase I inhibitors was compared concomitantly in two human colon xenograft models. In both models, GI147211 and GI149893 were able to induce regression of established HT-29 and SW-48 colon tumors by as much as 60%. The antitumor activity of both compounds were also demonstrated in the MX-1 and PC-3 xenografts. Microscopic examination of selected tissues indicated that drug-induced toxicity was primarily limited to the gastrointestinal tract and was comparable among the three compounds. Further clinical development of this class of compounds is ongoing.

Inactivation of visna virus and other enveloped viruses by free fatty acids and monoglycerides.

Human milk was found to become antiviral during storage at 4 degrees C because of the release of fatty acids by lipolysis. The stored milk caused more than a 10,000-fold inactivation of visna virus during incubation at 37 degrees C for 30 minutes. Medium-chain saturated and long-chain unsaturated fatty acids inactivated visna virus and other enveloped viruses causing more than a 3000-fold to 10,000-fold reduction in virus titer. 1-Monoglycerides and ethers of medium-chain fatty acids were more antiviral than the corresponding free fatty acids. Antiviral fatty acids were found to affect the viral envelope, causing leakage and, at higher concentrations, a complete disintegration of the envelope and the viral particles. Lipids commonly found in natural products could possibly be used as antiviral agents against enveloped viruses.

Chain pullout and mobility effects in friction and lubrication.

The interfacial shear stress that occurs when a network of a polymer that is highly mobile at the segment level (an elastomer) is slid over a smooth surface of an immobile (glassy) polymer has been measured. The glassy material is covered by a thin layer of end-attached chains of the mobile material. The experiment was designed so that there were no free chains at the interface; the slip occurred between network chains on the one side and rigid material plus end-attached mobile chains on the other side. Two main results were obtained. (i) The interfacial shear stress is strongly affected by the segment mobility of the materials on both sides of the slip plane, and considerably lower stress is observed when the materials on both sides of the interface are highly mobile. (ii) Very thin layers of tethered chains can increase the interfacial friction. Both results are relevant to the understanding of a number of practical situations that range from the operation of thin layers of lubricants, such as those found in magnetic storage devices, to the problem of wall slip and melt fracture in polymer processing.

Occupational and educational achievements of head injured Vietnam veterans at 15-year follow-up.

Little is known about the long-term affects of head injury on achievement. The post-injury educational and occupational achievements of 520 survivors of penetrating head injury in Vietnam (and 85 uninjured controls) were examined 15 years after injury. Most patients (82%) had used Veterans Administration educational benefits to return to school, and many of those (64%) had achieved degrees. Return to work was strongly related to level of educational achievement, particularly among the most severely disabled. Though only 56% of the head injured were gainfully employed, the occupational distribution of those who were working differed little from uninjured controls, or the male labor force. Severity of injury affects educational achievement and return to work, but not the occupational distribution of those who do manage to return. Even the most severely injured can sometimes achieve high educational and occupational levels.

Delayed acute measles inclusion body encephalitis in a 9-year-old girl: ultrastructural, immunohistochemical, and in situ hybridization studies.

A 9-yr-old girl developed delayed acute measles inclusion body encephalitis, which was different from subacute sclerosing panencephalitis (SSPE) in clinical course. Measles virus was demonstrated by electron microscopy, immunohistochemistry, and in situ hybridization. Contrary to the most previous reports, matrix (M) protein was present in the brain, cerebrospinal fluid, and serum and was demonstrated by Western blot analysis and in situ hybridization. The hybridization was performed by a nonradioactive digoxigenin method.

Radiographic and geometric anatomy of the scapula.

In an effort to study anatomic parameters of the scapula that may be of clinical importance, scapulae were harvested from cadavers and stripped of their soft tissues. For each scapula, three roentgenograms then were obtained: a Y-scapular view, an axillary lateral view, and a glenoid fossa (or true anteroposterior) view. Computed tomographic pneumoarthrograms and randomly selected antero-posterior chest roentgenograms of skeletally mature adults were studied also to measure further roentgenographic parameters of the normal scapula. The geometric anatomy of the scapula is of fundamental importance in the pathomechanics of rotator cuff disease, total shoulder arthroplasty, and recurrent shoulder dislocation. This study presents in detail the exact geometry of scapula anatomy, giving precise figures for distances, angles, and radii of curvature of the scapula. All results then are discussed in terms of their clinical relevance to the above problems.

Morphology of nasal lesions induced in Osborne-Mendel rats and B6C3F1 mice by chronic inhalation of allyl glycidyl ether.

Chronic (24-month) inhalation exposure to 5 or 10 ppm allyl glycidyl ether (AGE) induced nasal lesions in Osborne-Mendel rats and B6C3F1 mice. Inflammation, degeneration, regeneration, metaplasia, hyperplasia, and neoplasia were observed in the nasal mucosa. Squamous metaplasia and hyperplasia of the respiratory epithelium and degeneration and regeneration with subsequent squamous and/or respiratory metaplasia of the olfactory epithelium were observed in many AGE-exposed animals. Three primary nasal neoplasms (1 papillary adenoma, 1 squamous cell carcinoma, and 1 olfactory epithelial carcinoma) were observed in rats exposed to 10 ppm AGE, and 1 nasal papillary adenoma was observed in a rat exposed to 5 ppm. Four papillary adenomas and 2 hemangiomas were observed in the noses of mice exposed to 10 ppm AGE. Although the incidence of primary nasal tumors in AGE-exposed rats or mice was not statistically significant compared to the incidence in concurrent controls, the relative rarity of primary nasal tumors in historical controls and the concurrent presence of metaplastic and hyperplastic nasal lesions similar to those reported to be associated with induced tumors of nasal epithelia by other chemicals suggest that the nasal tumors observed may be related to AGE exposure. It was concluded that, in addition to lesions indicating a toxic effect on the nasal mucosa, inhalation exposure to AGE for 24 months resulted in some evidence of carcinogenicity of AGE for male mice, equivocal evidence of carcinogenicity for female mice and male rats, and no evidence of carcinogenicity for female rats.

Nearly ubiquitous tissue distribution of the scrapie agent precursor protein.

The "modified host protein" model of scrapie proposes that the transmissible agent is composed of the degradation-resistant protein, Sp33-37, and that clinical and pathologic signs result from neurotoxic accumulations of this protein. Sp33-37 is an abnormal, amyloidogenic isoform of the normally occurring cellular protein Cp33-37. This study investigated the tissue distribution of Cp33-37 in hamster. In brain, Cp33-37 was most concentrated in the hippocampal formation. Immunohistochemical studies localized Cp33-37 to neurons and surrounding neuropil in hippocampus; septal, caudate, and thalamic nuclei; dorsal root ganglia cells; and large-diameter dorsal root axons. In non-neuronal hamster tissues, Cp33-37 was detected in circulating leukocytes, heart, skeletal muscle, lung, intestinal tract, spleen, testis, ovary, and some other organs. The presence of Cp33-37 in extracerebral tissues indicates that its function is not unique to brain. These results indicate that the molecular substrate for the production of Sp33-37, the scrapie agent, and scrapie amyloid is present in a variety of cerebral and extracerebral sites.

Digital ranges of motion: normal values in young adults.

Analysis of the range of motion of fingers was done in young (eighteen to thirty-five year old) adult volunteers with no history of previous injury to their hands. The data show that there are slight differences between the individual digits. Notably, metacarpophalangeal flexion and total active motion increase linearly in proceeding from the index to the small finger. There were also minor differences in comparing sexes. Women have greater extension at the metacarpophalangeal joint in both active and passive motion and have a greater total active motion at all digits as a result. A significant tenodesis effect was found at the distal interphalangeal joint in normal subjects. No differences were found that could be attributable to handedness.

Proliferative and neoplastic lesions in the rodent nasal cavity.

Proliferative lesions in the rodent nasal cavity are reviewed; attempt was made to compare species affected, sex differences, strain differences, route of administration and tumor types occurring both spontaneously and after induction by different chemicals. This review is not meant to be all inclusive but to be representative of observed trends. Our general conclusions in this paper are that: 1) spontaneous nasal tumors in rodents are very rare; 2) spontaneous nasal tumors in rats are most often squamous cell tumors, whereas hemangiomas or respiratory adenomas predominate in mice and squamous cell tumors are rare; 3) rats are usually more susceptible to the induction of epithelial tumors of the nasal cavity than mice; 4) chemically-induced hemangiomas and hemangiosarcomas of the nasal cavity have only been reported in mice; 5) tumors of the olfactory epithelium are almost uniformly malignant and invasive, while nonsquamous tumors of the respiratory epithelium are typically less invasive; 6) chemically-induced tumors of the olfactory region, either mesenchymal or epithelial, do not always require an inhalation route of exposure but may occur by systemic targeting of this region; and 7) chemicals inducing tumors in the olfactory region often produce a variety of tumor morphologies in this location as well as squamous and polypoid tumors of the transitional region. More work will be needed to illucidate the mechanisms of nasal carcinogenesis and to further refine the current tumor classification system.

Comparative effects of growth irradiance on photosynthesis and leaf anatomy of Flaveria brownii (C4-like), Flaveria linearis (C 3-C 4) and their F 1 hybrid.

Photosynthetic rates and related anatomical characteristics of leaves developed at three levels of irradiance (1200, 300 and 80 umol · m(-2) · s(-1)) were determined in the C4-like species Flaveria brownii A.M. Powell, the C3-C4-intermediate species F. linearis Lag., and the F1 hybrid between them (F. brownii × F. linearis). In the C3-C4 and F1 plants, increases in photosynthetic capacity per unit leaf area were strongly correlated with changes in mesophyll area per unit leaf area. The C4-like plant F. brownii, however, showed a much lower correlation between photosynthetic capacity and mesophyll area per unit leaf area. Plants of F. brownii developed at high irradiance showed photosynthetic rates per unit of mesophyll cell area 50% higher than those plants developed at medium irradiance. These results along with an increase in water-use efficiency are consistent with an increase of C4 photosynthesis in high-irradiance-grown F. brownii plants, whereas in the other two genotypes such plasticity seems to be absent. Photosynthetic discrimination against (13)C in the three genotypes was less at high than at low irradiance, with the greatest change occurring in F. brownii. Discrimination against (13)C expressed as δ (13)C was linearly correlated (r (2) = 0.81; P<0.001) with the ratio of bundle-sheath volume to mesophyll cell area when all samples from the three genotypes were combined. This tissue ratio increased for F. brownii and the F1 hybrid as growth irradiance increased, indicating a greater tendency towards Kranz anatomy. The results indicated that F. brownii had plasticity in its C4-related anatomical and physiological characteristics as a function of growth irradiance, whereas plasticity was less evident in the F1 hybrid and absent in F. linearis.

Fordyce's granules of the incisor and molar gingiva in F344 rats.

Fordyce's granules were observed in the gingiva of the upper incisor and molar teeth in F344 rats. The data were based on 734 males and 722 females that were used as control and treated animals in 26-week, 65-week, and 2-year studies by the National Toxicology Program. The incidence of Fordyce's granules was markedly different when comparing sex, age, and site of the lesion. Fordyce's granules were very common in the midsagittal gingiva of the upper incisor in males and increased in incidence with age (34.2, 50, and 56.3% in 26-week, 65-week, and 2-year studies, respectively). The granules of the incisor gingiva were rare in females (0,0, and 2.8% in 26-week, 65-week, and 2-year studies, respectively). Fordyce's granules of the molar gingiva were very rare in both sexes and were found only in 9/734 (1.2%) males and in 3/722 (0.4%) females. Only three unilateral granules of the molar were grossly recognized as focal swelling of the gingiva or a white nodule with a huge cyst in the third upper molar. Histologically, Fordyce's granules were arranged as a collection of sebaceous glands unassociated with hair follicles. In addition, the granules of the molar gingiva were associated with cystically dilated ducts filled with sebum. Ultrastructurally, the sebaceous cells were characterized by varying numbers of cytoplasmic lipid droplets and occasional desmosome and hemidesmosome formation. Fordyce's granules previously reported in rats of other strains were also reviewed and compared with those in F344 rats in regard to incidence, location, and age.