Pteridine-2,4-diamine derivatives as radical scavengers and inhibitors of lipoxygenase that can possess anti-inflammatory properties

BACKGROUND: Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. The complex nature of inflammation and of oxidative stress suggests that dual-target agents may be effective in combating diseases involving reactive oxygen species. RESULTS: A novel series of N-substituted 2,4-diaminopteridines has been synthesized and evaluated as antioxidants in several assays. Many exhibited potent lipid antioxidant properties, and some are inhibitors of soybean lipoxygenase, IC50 values extending down to 100 nM for both targets. Several pteridine derivatives showed efficacy at 0.01 mmol/kg with little tissue damage in a rat model of colitis. 2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)pteridin-4-amine (18f) at 0.01 mmol/kg exhibited potent anti-inflammatory activity (reduction by 41%). CONCLUSION: The 2,4-diaminopteridine core represents a new scaffold for lipoxygenase inhibition as well as sustaining anti-inflammatory properties

N-Acylated and N-Alkylated 2-Aminobenzothiazoles Are Novel Agents That Suppress the Generation of Prostaglandin E2.

The quest for novel agents to regulate the generation of prostaglandin E2 (PGE2) is of high importance because this eicosanoid is a key player in inflammatory diseases. We synthesized a series of N-acylated and N-alkylated 2-aminobenzothiazoles and related heterocycles (benzoxazoles and benzimidazoles) and evaluated their ability to suppress the cytokine-stimulated generation of PGE2 in rat mesangial cells. 2-Aminobenzothiazoles, either acylated by the 3-(naphthalen-2-yl)propanoyl moiety (GK510) or N-alkylated by a chain carrying a naphthalene (GK543) or a phenyl moiety (GK562) at a distance of three carbon atoms, stand out in inhibiting PGE2 generation, with EC50 values ranging from 118 nM to 177 nM. Both GK510 and GK543 exhibit in vivo anti-inflammatory activity greater than that of indomethacin. Thus, N-acylated or N-alkylated 2-aminobenzothiazoles are novel leads for the regulation of PGE2 formation

The spine in Paget’s disease

Paget’s disease (PD) is a chronic metabolically active bone disease, characterized by a disturbance in bone modelling and remodelling due to an increase in osteoblastic and osteoclastic activity. The vertebra is the second most commonly affected site. This article reviews the various spinal pathomechanisms and osseous dynamics involved in producing the varied imaging appearances and their clinical relevance. Advanced imaging of osseous, articular and bone marrow manifestations of PD in all the vertebral components are presented. Pagetic changes often result in clinical symptoms including back pain, spinal stenosis and neural dysfunction. Various pathological complications due to PD involvement result in these clinical symptoms. Recognition of the imaging manifestations of spinal PD and the potential complications that cause the clinical symptoms enables accurate assessment of patients prior to appropriate management

Adjacent level discitis after anterior cervical discectomy and fusion (ACDF): a case report

This report describes a case of spondylodiscitis occurring adjacent to levels at which anterior cervical discectomy and fusion was performed. The objective is to describe a rare cause of spondylodiscitis and discuss its successful management. Post-operative discitis involving the same level is a known occurrence. We report an interesting case of spondylodiscitis occurring at the adjacent level of fusion, and to our knowledge this is the first such case reported in literature. A two-level decompression and fusion was performed at C5–6 and C6–7 levels with PEEK cages and anterior cervical plating in a middle-aged gentleman for persistent axial neck pain and left-sided radiculopathy involving C6 and C7 distribution. After 6 weeks, the patient presented to us with complaints of mild paresthesia in the abdomen and extremities. Radiological investigations including plain radiographs and MRI revealed a surprising finding of discitis at C4–5 level with an associated epidural abscess. In view of the patient’s myelopathic symptoms, surgical debridement and decompression of the spinal cord was performed. The plate and screws were removed, the cages were left intact, and the C4–5 disc level was reconstructed with tricortical iliac crest autograft. No further instrumentation was performed. The biopsy specimen from the disc at C4–5 level grew Serratia marcescens. It was contemplated that C4–5 discitis was initiated by inoculation of bacteria at the superior endplate of C5 by contaminated vertebral pins/drill-bit or screws. Adjacent level discitis is a rare but potentially serious complication of anterior cervical fusion. A high index of suspicion of infection is necessary if the patient complains of new symptoms after anterior cervical fusion. Thorough assessment and aggressive treatment is necessary for successful management

Impact of two myostatin (MSTN) mutations on weight gain and lamb carcass classification in Norwegian White Sheep (Ovis aries)

<p>Abstract</p> <p>Background</p> <p>Our aim was to estimate the effect of two <it>myostatin </it>(<it>MSTN</it>) mutations in Norwegian White Sheep, one of which is close to fixation in the Texel breed.</p> <p>Methods</p> <p>The impact of two known <it>MSTN </it>mutations was examined in a field experiment with Norwegian White Sheep. The joint effect of the two <it>MSTN </it>mutations on live weight gain and weaning weight was studied on 644 lambs. Carcass weight gain from birth to slaughter, carcass weight, carcass conformation and carcass fat classes were calculated in a subset of 508 lambs. All analyses were carried out with a univariate linear animal model.</p> <p>Results</p> <p>The most significant impact of both mutations was on conformation and fat classes. The largest difference between the genotype groups was between the wild type for both mutations and the homozygotes for the c.960delG mutation. Compared to the wild types, these mutants obtained a conformation score 5.1 classes higher and a fat score 3.0 classes lower, both on a 15-point scale.</p> <p>Conclusions</p> <p>Both mutations reduced fatness and increased muscle mass, although the effect of the frameshift mutation (c.960delG) was more important as compared to the 3'-UTR mutation (c.2360G>A). Lambs homozygous for the c.960delG mutation grew more slowly than those with other <it>MSTN </it>genotypes, but had the least fat and the largest muscle mass. Only c.960delG showed dominance effects.</p

Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents

We report the synthesis, anti-inflammatory and antioxidant activities of novel quinoxaline and quinoxaline 1,4-di-N-oxide derivatives. Microwave assisted methods have been used in order to optimize reaction times and to improve the yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase. Two of the best lipoxygenase inhibitors (compounds 7b and 8f) were evaluated as in vivo anti-inflammatory agents using the carrageenin-induced edema model. One of them (compound 7b) showed important in vivo anti-inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug

The epidemiology of hematogenous vertebral osteomyelitis: a cohort study in a tertiary care hospital

<p>Abstract</p> <p>Background</p> <p>Vertebral osteomyelitis is a common manifestation of osteomyelitis in adults and associated with considerable morbidity. Limited data exist regarding hematogenous vertebral osteomyelitis. Our objective was to describe the epidemiology and management of hematogenous vertebral osteomyelitis.</p> <p>Methods</p> <p>We performed a 2-year retrospective cohort study of adult patients with hematogenous vertebral osteomyelitis at a tertiary care hospital.</p> <p>Results</p> <p>Seventy patients with hematogenous vertebral osteomyelitis were identified. The mean age was 59.7 years (±15.0) and 38 (54%) were male. Common comorbidities included diabetes (43%) and renal insufficiency (24%). Predisposing factors in the 30 days prior to admission included bacteremia (19%), skin/soft tissue infection (17%), and having an indwelling catheter (30%). Back pain was the most common symptom (87%). Seven (10%) patients presented with paraplegia. Among the 46 (66%) patients with a microbiological diagnosis, the most common organisms were methicillin-susceptible <it>S. aureus </it>[15 (33%) cases], and methicillin-resistant <it>S. aureus </it>[10 (22%)]. Among the 44 (63%) patients who had a diagnostic biopsy, open biopsy was more likely to result in pathogen recovery [14 (93%) of 15 with open biopsy vs. 14 (48%) of 29 with needle biopsy; p = 0.003]. Sixteen (23%) patients required surgical intervention for therapeutic purposes during admission.</p> <p>Conclusions</p> <p>This is one of the largest series of hematogenous vertebral osteomyelitis. A microbiological diagnosis was made in only approximately two-thirds of cases. <it>S. aureus </it>was the most common causative organism, of which almost half the isolates were methicillin-resistant.</p