Metabolic and neurological consequences of the treatment with polyphenols: a systematic review in rodent models of noncommunicable diseases.

BACKGROUND: Noncommunicable diseases (NCDs) lead to drastic metabolic alterations with associated energy balance and body weight changes, two related physiological processes regulated by the brain. Polyphenol-based treatments for NCDs have emerged as a promising therapy, which seems to involve the energy balance modulation. However, it remains unclear what the most effective polyphenols-based treatment is to attenuate adverse effects in the energy balance of NCDs. OBJECTIVES: This systematic review aimed to evaluate the literature on the metabolic and neurological effects of polyphenols-based treatment in rodent models of NCDs. METHODS: Literature search was carried out in the following databases: CINAHL, Medline/PubMed, SCOPUS, and Web of Science. For title and abstract screening, original papers with polyphenols exposure in rodents were selected. For full-text screening, studies with models of NCDs that reported metabolic and neurological outcomes when treated with polyphenols were selected for inclusion in this review. RESULTS: 23 articles, using individual compound (11 articles) or polyphenols extracts (12 articles), were included in this review: 5 articles using tea polyphenols, 12 articles using grape-derived polyphenols, 3 articles using the polyphenol quercetin, and 3 articles using other polyphenol sources. Most results agree on the beneficial effect of polyphenols in attenuating alterations in energy balance and body weight. Such effects were associated with neuroprotective responses in different brain areas including hippocampus and hypothalamus. CONCLUSION: In conclusion, this review shows that the treatment with polyphenols, especially resveratrol or quercetin, attenuates the adverse effects of NCDs on energy balance and are associated with neuroprotective effects.

The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the dog.

The dog is a common model for study of osteoarthritis (OA). Subjective histologic scoring systems have often served as the reference standard for presence and severity of OA. However, these scoring systems have perceived shortcomings. The system developed for this report attempts to address these shortcomings by providing a standardized methodology for global assessment of the joint, versatility and the potential for relative weighting of pathology, allowing for comparison among time points, studies, and centers, and critical analysis of the system's reliability. The proposed system for assessment of canine tissues appears to provide an effective method for global assessment of articular pathology in OA. The system is versatile, comprehensive, and reliable and appears to have advantages over conventional scoring systems.

2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors.

Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-difluorophenyl derivative 7 (L-776,967) and the 3-pyridyl derivative 13 (L-784,506) are particularly interesting as potential antiinflammatory agents with reduced side-effect profiles. Both exhibit good oral bioavailability and are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonsteroidal antiflammatory drugs.

Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.

Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).

Neurogenic acceleration of osteoarthrosis. The effects of previous neurectomy of the articular nerves on the development of osteoarthrosis after transection of the anterior cruciate ligament in dogs.

The development of osteoarthrosis in unstable knee joints of dogs after transection of the anterior cruciate ligament is greatly accelerated when the afferent nerve fibers from the ipsilateral hindlimb have been interrupted by dorsal root ganglionectomy before transection. The purpose of the current study was to determine whether partial loss of the afferent fibers from the knee joints of dogs, accomplished by neurectomy of the primary articular nerves before transection of the ligament, also accelerates the development of osteoarthrosis. Osteoarthrosis did not develop in dogs that had had transection of the medial, posterior, and lateral articular nerves to the left knee joint but had an intact anterior cruciate ligament. Osteoarthrosis developed in all dogs that had had transection of the anterior cruciate ligament. However, the osteoarthrotic lesions, as gauged by histological and macroscopic criteria, were more frequent and severe in dogs that had had neurectomy before transection than in those that had intact sensory nerves and an unstable joint (p less than or equal to 0.05). A subchondral fracture occurred in three dogs that had had neurectomy and had an unstable joint but in none of the dogs that had intact sensory nerves and an unstable joint.

Relaxation of classical particles in two-dimensional anharmonic single-well potentials.

The canonical ensemble relaxation function of a particle in a symmetric anharmonic potential well in D=1 is known to exhibit slow algebraic behavior [S. Sen, R. S. Sinkovits and S. Chakravarti, Phys. Rev. Lett. 77, 4855 (1996); R. S. Sinkovits, S. Sen, J. C. Phillips, and S. Chakravarti, Phys. Rev. E 59, 6497 (1999)]. In the present work, we report a study of relaxation of a particle in symmetric and asymmetric quartic anharmonic potential wells of the form V(x,y)=1 / 2 (x(2)+Cy2)+1 / 4 (x(2)+Cy2)(2) in D=2. The relaxation in the above system is identical to that in D=1 wells when C=0 (since it is then a D=1 system) and C=1. However, for 0>1, the frequencies associated with well dynamics are strongly affected and hence the power spectra are altered as a function of C. Our calculations suggest that the exponents of the long-time tails associated with the relaxation processes are insensitive to D. In closing, we comment on the consequences of our analysis for the study of slow dynamics in interacting many-particle systems that are connected by harmonic springs with the individual particles in anharmonic potential wells.

Ground reaction force profiles from force platform gait analyses of clinically normal mesomorphic dogs at the trot.

Force platform analysis of gait provides ground reaction force information that can be used to study limbs with normal or abnormal function. When combined, the interrelated variables of ground reaction forces give a more thorough description of gait than when used individually. To describe the pattern of ground reaction forces in clinically normal, conditioned, mesomorphic dogs, we studied the data from platform gait analyses of 43 dogs. Mediolateral (Fx), craniocaudal (Fy), and vertical (Fz) forces were measured and recorded. Torque (Tz) around the vertical axis also was calculated. Mean stance times for forelimbs and hind limbs were 0.278 and 0.261 second, respectively. Among dogs, ground reaction forces were normalized and expressed as percentage of body weight (%bw). The vertical (Fz) peak, average force during stance phase, and force vs time impulses were 106.68, 60.82, and 17.2 %bw in forelimbs, and were 65.11, 35.3, and 9.33 %bw in hind limbs. The forelimb braking/propulsive (Fy) peaks were -16.74 and +6.73 %bw. In hind limbs, these peaks were -3.76 and +7.69 %bw. The usual mediolateral force (Fx) pattern found in forelimbs was laterally directed, with average peak magnitude of 6.69 %bw, whereas the hind limb patterns were variable.

Vertical ground reaction force distribution during experimentally induced acute synovitis in dogs.

The pattern of vertical ground reaction force redistribution among limbs during episodes of acute synovitis of the stifle in 12 mixed-breed dogs was investigated as an adjunct to a blinded nonsteroidal anti-inflammatory drug efficacy study. Without regard to drug efficacy groupings, the redistribution of vertical forces before and during the acute synovitis episode was evaluated by analysis of gait, using a force platform. Acute synovitis was induced by intrasynovial injection of sodium urate crystals. Simultaneously, each dog was given 1 of 4 treatment regimens, including IV injection of sterile saline solution (as a negative control), phenylbutazone (as a positive control), or 1 of 2 proprietary nonsteroidal anti-inflammatory drugs. Postinjection analyses took place at 2, 4, 8, 12, 24, and 36 hours. The peak vertical force redistribution in the 3 untreated limbs of the dogs was described. The greatest redistribution was observed 4 hours after substance injection when the synovitis was clinically at maximum. Thereafter, there was steady improvement and the dogs had a clinically normal gait 24 hours after substance injection. During synovitis, peak vertical force increased in the contralateral hind limb. During the more severe synovitis episodes, force was decreased in both forelimbs. There was good correlation between severity of lameness and peak vertical force response in the contralateral hind limb. Results of the study indicate that the untreated limbs of the same animal should not be used as a control during acute lameness studies.

Use of histochemical techniques in the characterisation of osteochondroses affecting pigs.

Growth cartilages with dyschondroplastic foci (osteochondrosis) or areas of chondrolysis were selected from the ribs and bones of the appendicular skeleton of 132 commercial pigs euthanased between one and 169 days old or at a liveweight of 100 kg. Histochemical staining techniques that identified proteoglycans, collagen and deposits of calcium enhanced the visualisation of the lesions, were valuable for recognising the distribution of lesions, and helped to elucidate the development of the lesions. On the basis of the histochemical and morphological differences, it was considered that the lesions associated with growth plates and the lesions associated with articular-epiphyseal cartilage complexes should be considered as different entities. Lesions were identified in the articular-epiphyseal cartilage complexes of pigs at 15 days old, earlier than has been reported previously. Toluidine blue and safranin O were more useful than alcian blue and, in terms of staining intensity, toluidine blue gave more consistent results than safranin O.

Cartilage canals and lesions typical of osteochondrosis in growth cartilages from the distal part of the humerus of newborn pigs.

Vessels in cartilage canals supplying the articular-epiphyseal cartilage complex and growth plate of the distal part of the humerus of pigs between on day and 15 weeks old were examined in perfused and cleared specimens, and histochemical preparations. An extensive capillary network surrounded the arterioles and venules and probably maintained the circulation of blood as the ends of the cartilage canals underwent involution. Pits and grooves were in predilection sites for osteochondrosis and osteoarthrosis and were typical of early lesions of these conditions. Some ghosts that were observed mesoscopically were chondrified cartilage canals or remnants of cartilage canals in histological sections, and were considered to be the result of a normal process. However, abnormal involution may predispose to chrondrolysis, and the presence of involuting transverse cartilage canals at predilection sites implicated damaged canals in the aetiopathogenesis of osteochondrosis and osteroarthrosis in some pigs. Cleared specimens provided the most useful demonstration of the form and distribution of cartilage canals, ghosts, and pits or grooves. The association of cartilage canals with areas of chondrolysis, and the distribution of ghosts in the predilection sites for lesions, warrant further investigation of blood vessels within cartilage canals.

Arterial oxygen saturation in sedated patients undergoing gastrointestinal endoscopy and a review of pulse oximetry.

The pulse oximeter is a widely used noninvasive monitor which provides a continuous reading of arterial oxygen saturation. We sought to determine if patients with cardiopulmonary disease were at higher risk of oxygen unsaturation than controls during gastrointestinal endoscopy. Patients presenting for upper gastrointestinal endoscopy and/or colonoscopy were placed into one of two groups: A. control population:patients with no history of cardiac and/or pulmonary disease (N = 11); B. test population:patients with a history of cardiac and/or pulmonary disease (N = 39). The procedure was performed by one of 14 equally experienced physicians. The Nellcor N-100 Pulse Oximeter and D-25 finger probe were used to monitor arterial oxygen saturation which was recorded at five minute intervals from commencement of intravenous sedation analgesia to 15 minutes post-procedure. In both groups, the oxygen saturation fell to statistically significant. A: 98.3% to 90.2%; B: 97.7% to 89.5%. However, the amount of unsaturation which occurred in Group B was not statistically different from Group A. Therefore, history of prior cardiac and/or pulmonary disease does not increase the degree of unsaturation from that occurring in patients with no such history. In addition, the effects of age, procedure, duration, I.V. sedation, and individual tolerance on oxygen unsaturation were studied by regression analysis and analysis of variance (ANOVA). Only the upper GI endoscopy patients showed a dependence of oxygen unsaturation upon one of the variables, specifically patient tolerance. It is concluded that patients at risk for hypoxemia during endoscopy or colonoscopy cannot be determined prior to the initiation of the procedure, and it is recommended that all of these patients be given supplemental oxygen as well as monitored with a pulse oximeter.

Monoclonal antibodies that detect biochemical markers of arthritis in humans.

OBJECTIVE: To evaluate the potential of using monoclonal antibodies (MAb) 3-B-3(-) and 7-D-4 to detect biochemical markers of altered cartilage metabolism in human arthritides. METHODS: Fifty-five samples of normal articular cartilage (subjects' age range 18 weeks of gestation to 83 years of age) and 89 samples of arthritic cartilage (patients' age range 20-81 years) were collected, and their proteoglycans were extracted and analyzed for the presence of the epitopes recognized by MAb 3-B-3 and 7-D-4. RESULTS: Native 3-B-3(-) mimotope was expressed at a high incidence in proteoglycans extracted from the cartilage of patients with most of the arthritic diseases examined (osteoarthritis, juvenile rheumatoid arthritis, rheumatoid arthritis, avascular necrosis, and degenerative meniscal tears). Its expression in normal cartilage specimens was very low or absent, occurring mainly in the young, skeletally immature individuals. In contrast, expression of the 7-D-4 epitope was more variable in patients with different arthritides and was also frequently found in normal cartilage specimens. Immunohistochemical analyses with both 3-B-3(-) and 7-D-4 showed strong focal positive staining in superficial areas, where cartilage degeneration, remodeling, and repair were greatest. CONCLUSION: The biochemical markers recognized by MAb 3-B-3(-) and 7-D-4 are indicative of altered proteoglycan synthesis and metabolism in human articular cartilage. The data suggest that in human cartilage, the 3-B-3(-) epitope might be a better marker of biochemical changes than the 7-D-4 epitope.

A matrix metalloproteinase-generated aggrecan neoepitope as a marker of skeletal maturation and aging in cartilage.

OBJECTIVE: To quantify the matrix metalloproteinase-induced neoepitope F(M/V)DIPEN (Phe-[Met/Val]-Asp-Ile-Pro-Glu-Asn341) in guinea pig and rabbit cartilage during aging. METHODS: Cartilage was taken from the stifle joint, nasal septum, and xiphoid process in guinea pigs and rabbits at selected ages. The cartilage was then extracted and evaluated for F(M/V)DIPEN levels by radioimmunoassay. RESULTS: In the 3 tissues studied, there were major increases in F(M/V)DIPEN levels during skeletal maturation and aging in both the guinea pig and rabbit cartilage. Except for spontaneous osteoarthritis that develops in guinea pigs with aging, increases in the neoepitope were not correlated with arthritis pathology. CONCLUSION: Increases in the level of F(M/V)DIPEN in cartilage occur as a result of skeletal maturation and aging. This physiologic accumulation of F(M/V)DIPEN in cartilage should be considered when using the neoepitope as a disease marker in arthritis.

Experimental osteoarthritis in dogs: a comparison of the Pond-Nuki and medial arthrotomy methods.

Lesions induced by transecting the cranial cruciate ligament in two surgical models of osteoarthritis (OA) in mature, male, cross-bred dogs were compared by using an established grading system and alternatives. Previously, we relied on evaluations of lesions in articular cartilage on femurs alone. No statistically significant differences were found between grades for lesions in cartilage when either treated or control joints were compared by surgical method. Because the Pond-Nuki method yielded statistically significant differences between grades for lesions affecting treated and control femurs or tibias, and for some parameters indicative of synovitis, we preferred this method of surgery. Although by using the medial arthrotomy method of surgery, we were able to destabilize the joint in a more consistent manner, significant differences between treated and control joints were found for lesions on tibias, but not femurs, a frequent site for OA in humans. Suggestions are made for enhancing the surgical models and for a more holistic approach to evaluating joints morphologically.

The effects of beveling the margins of articular cartilage defects in immature dogs.

Eight 4 month old crossbred puppies underwent surgery simulating treatment of osteochondritis dissecans. Both humeral heads were exposed by a caudal approach to the shoulder joint. In one, an 8 mm circular, full-thickness cartilage defect was created so that the remnant cartilage margin was perpendicular to the joint surface. In the other, a similar 8 mm defect was created with the chondral margins beveled at approximately 45 degrees. There was no clinical lameness in any of the dogs. At necropsy after 16 weeks, the cartilage defects with beveled edges were significantly larger (11.0 +/- 0.6 mm SD) than those with perpendicular edges (8.0 +/- 0.1 mm SD), because of the beveling (p = 0.0039). Fibrocartilage was present but did not always completely fill the defects. Articular surfaces of the glenoid cavities suffered erosion and fibrillation more frequently opposite beveled defects than opposite defects with vertical walls (p = 0.0312). This was presumably due to the larger apposing defect. It was concluded that the cartilage margins surrounding a chondral defect should not be beveled.

The vascular supply of the chondro-epiphyses of the elbow joint in young swine.

The vasculature of the elbow joint was examined in 39 pigs between one day and 15 weeks of age. Each pig was anaesthetised, exsanguinated and the thoracic limbs were perfused with India ink or a silicone rubber injection compound. The humerus, ulna and radius were dissected free, examined, fixed in formalin or ethyl alcohol, cleared by the modified Spalteholz technique and examined mesoscopically. Features of interest were photographed and then a limb from two pigs in each age group was cut into slabs and examined mesoscopically. The vascular supply of the distal part of the humerus was complex. It was supplied by vessels on both the cranial and caudal aspects and locally each aspect had a dual blood supply. Vessels anastomosed and on the cranial aspect formed a vascular ring. The proximal part of the ulna was supplied by vessels that were on its medial and lateral surfaces. The vessel on the lateral surface continued distally and supplied the lateral aspect of the proximal part of the radius. The proximal part of the radius was also supplied by arteries that were on the cranial and medial surfaces. Blood vessels provided branches to numerous cartilage canals of the articular-epiphyseal cartilage complexes, epiphyseal centres of ossification, and growth plates. The patterns of blood vessels in cartilage canals which were in sagittal or transverse planes were best exemplified by those in the distal part of the humerus. Perforating cartilage canals emerged from the epiphyseal centres of ossification. The pattern of cartilage canals was consistent in a general configuration, but individual variation did occur. Although cartilage canals were abundant in the youngest pigs, with increasing age the distribution of cartilage canals changed and the numbers of cartilage canals decreased.

The development of centres of ossification of bones forming elbow joints in young swine.

Epiphyseal centres of ossification in the bones forming the elbow joints of pigs between one day and 15 weeks of age were examined radiographically, macroscopically, mesoscopically and microscopically. Thoracic limbs from 39 pigs were perfused with India ink or silicone rubber injection compound and the bones were dissected free of soft tissues. The humerus, ulna and radius were fixed in formalin or ethyl alcohol and then cleared by the modified Spalteholz technique. Bones were radiographed, examined grossly, and then cut into slabs for mesoscopical evaluation. Foci considered to be calcifying within cartilaginous anlage were selected for microscopical examination. It was concluded that the epiphyseal centre of ossification develops at different times in different sites in the bones forming the elbow joint. Centres of ossification are initiated when foci of chondrocytes adjacent to one side of a cartilage canal undergo hypertrophy and the inter-territorial matrix becomes calcified. Osteogenesis then proceeds in the calcified focus, presumably with osteoprogenitor cells that originate within the cartilage canals. Subsequently, each epiphyseal centre of ossification enlarges by one of two methods. Firstly, the layer of cartilage adjacent to the centre undergoes endochondral ossification, thus allowing for the circumferential growth of the epiphyseal centre of ossification. Secondly, foci of calcification develop adjacent to the ends of cartilage canals near the epiphyseal centre of ossification and eventually the focus of calcification coalesces with the developing epiphyseal centre of ossification, thus establishing a new ossification front. Endochondral ossification continues at the periphery of the mass of bone. Mesoscopical examination is more useful than radiographical evaluation for identifying small foci of calcification which precede epiphyseal centres of ossification.