Arthritis, a complex connective and synovial joint destructive autoimmune disease: animal models of arthritis with varied etiopathology and their significance.

Animal models play a vital role in simplifying the complexity of pathogenesis and understanding the indefinable processes and diverse mechanisms involved in the progression of disease, and in providing new knowledge that may facilitate the drug development program. Selection of the animal models has to be carefully done, so that there is morphologic similarity to human arthritic conditions that may predict as well as augment the effective screening of novel antiarthritic agents. The review describes exclusively animal models of rheumatoid arthritis (RA) and osteoarthritis (OA). The development of RA has been vividly described using a wide variety of animal models with diverse insults (viz. collagen, Freund's adjuvant, proteoglycan, pristane, avridine, formaldehyde, etc.) that are able to simulate/trigger the cellular, biochemical, immunological, and histologic alterations, which perhaps mimic, to a great extent, the pathologic conditions of human RA. Similarly, numerous methods of inducing animal models with OA have also been described (such as spontaneous, surgical, chemical, and physical methods including genetically manipulated animals) which may give an insight into the events of alteration in connective tissues and their metabolism (synovial membrane/tissues along with cartilage) and bone erosion. The development of such arthritic animal models may throw light for better understanding of the etiopathogenic mechanisms of human arthritis and give new impetus for the drug development program on arthritis, a crippling disease.

Hypolipidemic and antioxidant activity of ethanolic extract of Symplocos racemosa Roxb. in hyperlipidemic rats: an evidence of participation of oxidative stress in hyperlipidemia.

Hypolipidemic and antioxidant activity profiles of ethanolic extracts of Symplocos racemosa (EESR) were studied by triton-WR1339 (acute) and high fat diet induced (chronic) hyperlipidemic rat models. In both the models, a significant increase in total cholesterol (TC), triglycerides (TG), very low density lipoproteins (VLDL), low density lipoproteins (LDL) and decrease in high density lipoproteins (HDL) in serum were observed. EESR (200 and 400 mg/kg) and simvastatin (10 mg/kg) administered orally reduced the elevated serum lipids (TC, TG, VLDL, LDL), restored the decreased HDL and improved the atherogenic index. In high fat diet induced hyperlipidemic model, EESR treatment prevented the increased formation of malondialdehyde (MDA) in liver, restored the depleted liver antioxidants, glutathione, superoxide dismutase, catalase significantly. The increased liver cholesterol, HMG-CoA reductase activity and body weight of hyperlipidemic rats were significantly reduced by EESR treatment. The EESR inhibited HMG-CoA reductase, a rate limiting enzyme in cholesterol biosynthesis, thereby causing hypolipidemic effects. EESR treatment also improved histoarchitecture of hepatocytes in hyperlipidemic rats. Experimental findings demonstrated anti-hyperlipidemic and antioxidant activity of EESR, which may be directly or indirectly related to its antioxidant activity. The hypolipidemic activity of EESR may be due to the presence of flavonoids phenolic compounds, phenolic glycosides and steroids.

Enhancement in the magnetic moment with Cr3+ doping and its effect on the magneto-structural properties of Ce(0.1)Y(2.9)Fe5O12.

A change in the overall magnetic moment of Cr(3+) doped cubic garnet ferrites prepared by the modified sol-gel auto combustion method has been investigated. A systematic Crystal Field Theory (CFT) approach is utilized towards understanding this variation in the overall magnetic moment. The malate glycolate precursor obtained in the sol-gel autocombustion method proves to be efficient in the monophasic preparation of the garnet system. X-Ray Diffraction (XRD) confirms the phase formation and purity. X-ray Photoelectron Spectroscopy (XPS) and Raman spectroscopy have been utilized to confirm the valence states of the elements and monophasic formation of the compounds. A change in the magnetic hyperfine field with doping is revealed by Mossbauer Spectroscopy. A Vibrating Sample Magnetometer (VSM) has been employed to probe the change in the magnetic properties with the change in the composition and temperature. The decrease in the magnitude of the antiferromagnetic interaction at a and d sites, with the inclusion of Cr(3+) at the a site and a contribution of L-S coupling from the Cr(3+) ions towards an increase in the resultant magnetic moment, is the significant finding of this investigation.

Anti-inflammatory, antiarthritic and analgesic activity of a herbal formulation (DRF/AY/4012).

Anti-inflammatory, antiarthritic and analgesic effect of a herbal product (DRF/AY/4012) was evaluated in animal models. Herbal product treatment induced a dose dependent anti-inflammatory activity in acute inflammatory models (carrageenin and egg-albumin induced rat hind paw edema). It also elicited promising anti-inflammatory activity in chronic inflammatory models (cotton pellet granuloma and Freund's adjuvant induced polyarthritis in rats). Further, the product inhibited the increased level of serum lysosomal enzyme activity viz. serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase and the lipid peroxidation in liver. In Freund's adjuvant induced polyarthritis, herbal product reduced the increased level of hydroxy proline, hexosamine and total protein content in edematous tissue. The product also exhibited mild to moderate analgesic activity in acetic acid induced writhing in mice. The LD50 value of the herbal product was more than 16 gm/kg by oral route in mice. The product has distinct advantages over the existing agents and deserves further developmental studies.

9-beta-D-arabinofuranosyladenine 5'-phosphate metabolism and excretion in humans.

9-beta-D-Arabinofuranosyladenine (ara-A) was converted chemically to the 9-beta-D-arabinofuranosyladenine 5'-phosphate (ara-A-5'-P) and administered i.v. to four cancer patients in seven experiments. Urinary excretion and plasma levels of radioactivity were monitored for 24 hr in each case. Radioactivity present as unchanged ara-A-5'-P, ara-A, and the deamination product of ara-A, 9-beta-D-arabinofuranosylhypoxanthine, was determined. Excretion was, as in earlier studies with ara-A, given i.v., largely as 6-beta-D-arabinofuranosylhypoxanthine. However, in contrast to the 88 to 97% excretion of ara-A and products in 24 hr when ara-A was given by i.v. push, excretion was 41.47 to 79.1% in 24 hr when ara-A-5'-P was given. With the exception of one experiment at a low dose, where plasma ara-A levels were significant for 6 hr, the plasma levels of ara-A were sustained at significant levels for 24 hr after a single dose of ara-A-5'-P. The doses of ara-A-5'-P given were well tolerated by the four patients. Indications are that this derivative provides important advantages (solubility and sustained blood levels) over ara-A.

Effect of energy dependence of primary beam divergence on the X-ray standing wave characterization of layered materials.

Incident primary beam divergence is a source of systematic error in X-ray standing wave (XSW) characterization of single and multilayer thin films. Primary beam divergence significantly alters the XSW profile of a layered material and can lead to large errors when used with higher excitation energies. The present study suggests that when one uses Mo-Kalpha excitation, the primary beam divergence should be in range of 0.005(0). On the other hand, in the case of Cu-Kalpha excitation, primary beam divergence can be relaxed up to 0.01(0).

Antibacterial action of doped CoFe2O4 nanocrystals on multidrug resistant bacterial strains.

The bactericidal effect of pristine and doped cobalt ferrite nanoparticles has been evaluated against multiple drug resistant clinical strains by assessing the number of colony-forming units (CFU). Monophasic polycrystalline ferrites have been prepared by the malate-glycolate sol-gel autocombustion method as confirmed by the X-ray diffraction study. Various changes occurring during the preparative stages have been demonstrated using TG-DTA analysis which is well complemented by the FTIR spectroscopy. The antibacterial studies carried out demonstrate a bactericidal effect of the nanoparticles wherein the number of CFU has been found to decrease with doping. Cellular distortions have been revealed through SEM. Variation in the number of CFU with dopant type has also been reported herein.

Effect of chronic tobacco-betel-lime "quid" chewing on human salivary secretions.

Salivary flow rates by mechanical stimulation with forced spitting method and by chemical stimulation with 10% citric acid were determined in 25 healthy adult subjects with a history of chronic tobacco-betel-lime "quid" chewing and in 25 healthy control adults with no history of chewing. The chewers secreted more saliva as compared to nonchewers on chemical, but not on mechanical stimulation. The salivary amylase, potassium, and sodium levels were lower in chewers, but the reductions of the first two components only were significant. These reductions were thought to be due to increased salivary flow with its dilutional effect. There was no difference between the two groups with respect to salivary pH. The salivary flow rates by either method had significant positive correlation with the duration of chewing, but not with the amount of tobacco chewed. Salivary potassium was inversely correlated with the amount of tobacco chewed. It was concluded that chronic tobacco-betel-lime quid chewing induces excessive secretion of more watery saliva leading to a concomitant decrease in enzyme and electrolyte content. One or more of the following factors were considered to be operating in causing increased salivary flow in chewers effect of nicotine or tobacco on other constituents of the quid, chronic salivary gland hyperplasia, or chronic hypertrophy of the muscles of mastication.

Involvement of gamma-amino butyric acid (GABA) in the anticonvulsant action of methaqualone.

The effects of methaqualone on isonicotinic acid hydrazide, 6-mercapto propionic acid, picrotoxin, and strychnine-induced convulsion were studied in mice and the results compared with diazepam. Methaqualone, like diazepam, was found to be a selective antagonist of isoniazid-induced convulsion and a much less effective inhibitor of strychnine convulsion. Methaqualone elicits muscle-relaxant, sedative, and anticonvulsant effects at different dose levels. At low, nonsedative doses the drug produces anticonvulsant effects, and at higher doses, muscle-relaxant and sedative effects. It appears that the mechanism(s) of action of methaqualone in on GABA deficiency or receptor blockade, rather than on glycine receptors.

Attenuation of stereotyped behaviour by sex steroids.

Effects of sex steroids, testosterone, progesterone, and estradiol on PEA-induced stereotyped behaviour (SB) has been studied in normal, castrated, and ovariectomised mice. Effects of sex steroids on amphetamine-induced sterotypy and hyperactivity are also described. In castrated and ovariectomised mice B-phenylethylamine (PEA) increased SB. Pretreatment with sex steroids attenuated PEA-induced stereotypy in normal, castrated, and ovarietomised mice. Sex steroid pretreatment significantly inhibited PEA- and amphetamine-induced SB, but failed to alter increased motor activity due to amphetamine or PEA. The possible effect of sec steroids on SB through changes in central neurotransmitters are discussed.

Possible involvement of 5-hydroxytryptamine and cyclic-AMP in tolerance to tremorine analgesia in mice.

The phenomenon of tolerance to the analgesic action of tremorine in mice was studied by the hot-plate and tail-clip methods. Reduction in 5-HT levels in brain by parachlorophenylalamine pretreatment decreased the ED50 of tremorine analgesia in tremorine tolerant mice. 5-Hydroxyptophan, L-Dopa or alpha-methyl-para-tyrosine did not influence the analgesic response to tremorine in tremorine tolerant animals. However, theophylline was found to enhance the tolerance to tremorine analgesia. Brain 5-HT and cAMP are probably involved in tremorine tolerance, whereas neither noradrenaline nor dopamine is involved in the phenomenon.

Effect of muscimol, a central GABA receptor agonist, on the catalepsy, striatal homovanillic acid increase, and analgesia induced by pilocarpine in rats.

Muscimol, a structural analog of GABA, significantly potentiated pilocarpine-induced analgesia in rats, but failed to alter pilocarpine-induced catalepsy. It also failed to affect pilocarpine-elicited increase in homovanillic acid levels in the striatum. These findings suggest that the potentiation of pilocarpine-induced analgesia by muscimol is unrelated to an interaction of the GABAergic system with the striatal cholinergic or dopaminergic systems.

Increased cyclic AMP-phosphodiesterase activity during inflammation and its inhibition by anti-inflammatory drugs.

Cyclic AMP-phosphodiesterase (cAMP-PDE) activity was determined in edematous and granulomatous tissues in carrageenin hind paw edema and cotton pellet granuloma of rats. In the time course study, maximum cAMP-PDE activity was observed in edematous tissue at 3-6 h after carrageenin injection and in granulomatous tissue from the 7th day onwards after cotton pellet implantation. Pretreatment with anti-inflammatory drugs inhibited significantly the increase in cAMP-PDE activity in edematous and granulomatous tissues. It was also observed that the increase in cAMP-PDE activity in edematous tissue paralleled the increase in migrated cells (leukocytes). Therefore, it is possible that the inhibition of cAMP-PDE activity by anti-inflammatory drugs may be the result of inhibition of cellular infiltration into the inflammatory site. It is suggested that phosphodiesterase may be an additional biochemical parameter for assessing cellular events of inflammation and consequently useful for the evaluation of anti-inflammatory drugs.

Pimprinine, an extracellular alkaloid produced by Streptomyces CDRIL-312: fermentation, isolation and pharmacological activity.

Pimprinine, an extracellular alkaloid has been isolated from the culture filtrate of Streptomyces CDRIL-312. Pimprinine was subsequently purified using silica gel column chromatography and also by preparatory thin layer chromatography. Some physicochemical properties, antimicrobial activities (in-vitro) and pharmacological activities of pimprinine were studied. Pimprinine showed promising anticonvulsant activity in both minimum and maximum electric seizure threshold test in mice. Its anticonvulsant activity is very much comparable to that of phenyl hydantion sodium. Pimprinine also inhibited effectively tremorine-induced tremors and analgesia in mice.

Virulence of Entamoeba histolytica in rat and its comparison with the serological responses of the amoebic patients.

The virulence of 70 isolates of Entamoeba histolytica was studied in the Wistar strain of albino rat by intracaecal inoculation of amoebae. The results were evaluated by the Neal scoring system, histopathological grading of ulcers and virulence indices. It was found that isolates from acute amoebic cases could infect and produce ulcers in significantly more animals than could the isolates from asymptomatic cyst passers. The virulence indices of isolates from acute cases were also significantly higher as compared to those from asymptomatic cyst passers. However, there was no significant difference between virulence indices of isolates from acute cases and non-dysenteric amoebic colitis. This study also showed that Neal scores failed to correlate with the type of pathology produced by the amoebae in the caecum. It is felt that virulence indices which depend upon the histopathological lesions should also be taken into consideration. The serological response of the patients tended to correlate with the virulence indices of isolates but only minimally. The results thus contradict a common belief amongst clinicians that higher levels of anti-amoebic antibodies reflect severe disease, as compared to low levels of antiamoebic antibodies.

Kala-azar in north-western India: a study of 24 patients.

Twenty-four sporadic cases of kala-azar diagnosed over an 11-year period in a referral medical centre in north-western India are reported. Most of the patients were residents of non-endemic areas or where endemicity was low. Certain unusual clinical and laboratory features were seen in some of the cases, namely, lymphadenopathy, nasopharyngeal growth, acute and chronic hepatic involvement and portal hypertension. Awareness of the occurrence of the disease and of its protean modes of presentation was found to be an important factor in early diagnosis.

Visceral leishmaniasis masquerading as a nasopharyngeal tumour. Report of a case.

A 55-year-old male, a resident of a village in the foothills of the Himalayas in the north-western region of India, presented with a huge nasopharyngeal tumour but was subsequently found to be infected with Leishmania donovani, involving the nasopharyngeal tissue and the draining lymph nodes as well as a visceral infection.

Moderate protective effect of 6-MFA, a microbial metabolite obtained from Aspergillus ochraceus on immunological liver injury in mice.

Hepatoprotective effect of 6-MFA, obtained from fungus Aspergillus ochraceus ATCC 28706, was evaluated by employing three different immunological liver injury mice models. The first liver injury model was induced by injecting anti-basic liver protein (BLP) antibody into mice previously immunised with rabbit IgG (RGG). The other models were simulated by injecting antiliver specific protein (LSP) antibody or by injecting bacterial lipopolysaccharide (LPS) into mice pretreated with Corynebacterium parvum (C. parvum). 6-MFA treatment inhibited the increased transaminases (GOT and GPT) activities and showed a tendency to inhibit the histopathological changes of the liver in all the models studied. Furthermore, 6-MFA treatment inhibited deoxycholic acid induced transaminase release from cultured rat hepatocytes in vitro, but failed to affect the formation of hemolytic plaque forming cells in immunised mice spleens and hemolytic activity of guinea pig complement in immunohemolytic reaction. Our findings, therefore, suggested that the moderate hepatoprotective effect of 6-MFA could be related to it's protective effect on hepatocyte plasma membrane rather than the direct inhibitory effects on the antibody formation and/or complement activity.

Experimental studies (in vitro) on polyene macrolide antibiotics with special reference to hamycin against Malassezia ovale.

Hamycin activity (in vitro) against Malassezia ovale was studied and compared with old and newly discovered polyene antifungal antibiotics. Hamycin showed a marked anti-M. ovale activity which was enhanced in the presence of divalent cations like Cu++ and Zn++. Furthermore, the absorption of hamycin onto the cell membrane or cell surface of M. ovale was also increased in the presence of divalent cations. It is suggested that hamycin alone or along with metal ions, specifically Cu++ may be useful clinically in the treatment of dandruff or seborrheic dermatitis.

Assessment of enzyme linked immunosorbent assay based diagnostic kits (Toxokit-G and Toxokit-M) for the detection of IgG and IgM antibodies to Toxoplasma gondii in human serum.

An enzyme linked immunosorbent assay (ELISA) using penicillinase was developed in the form of diagnostic kits (Toxokit-G and Toxokit-M) for the detection of IgG and IgM antibodies to Toxoplasma gondii. The performance of both the kits was compared with commercially available diagnostic kits, i.e. Enzygnost-Toxoplasmosis/IgG (Behring Co., Germany), TOXOTEK-G (Flow Lab., U.K.) and Toxoplasma IgM Microassay (Diamedix Corp., U.S.A.) by testing toxoplasma-suspected human serum samples. The results indicate a good reliability between these diagnostic kits. Toxokit-G has 86.66 and 96.05% sensitivity and specificity respectively. The main advantage of Toxokit-G is that the end result can be assessed visually without using sophisticated instruments. Toxokit-M has 100% sensitivity and specificity and test results were not affected by the presence of antitoxoplasma IgG antibodies, rheumatoid factor or antinuclear antibodies.