Pharmacological modulation by celecoxib of cachexia associated with experimental arthritis and atherosclerosis in rabbits

BACKGROUND AND PURPOSE

Non-steroidal anti-inflammatory drugs improve inflammatory cachexia in several conditions. Thus, we have explored inhibition of cyclooxygenase-2 (COX-2) in an experimental model of rheumatoid cachexia in rabbits.

EXPERIMENTAL APPROACH

Chronic arthritis was induced in immunized rabbits by repeated intra-articular injections of ovalbumin. To increase the degree of systemic inflammation and also to induce atherosclerotic lesions, the animals were fed a hyperlipidaemic diet (2% cholesterol and 6% peanut oil) and were given an endothelial injury of the femoral artery. Rabbits were randomized to receive the COX-2 inhibitor celecoxib (10 mg·kg⁻¹·day⁻¹) or no treatment. After 4 weeks, sera, peripheral mononuclear cells and vessel specimens were collected.

KEY RESULTS

Inhibition of COX-2 by celecoxib modulated the systemic inflammatory response and increased total cholesterol and triglyceride levels. Celecoxib also minimized weight loss and prevented serum albumin fall. At a vascular level, celecoxib reduced COX-2 protein in the femoral arterial wall, but did not modify size or the macrophage infiltration of femoral lesions nor the percentage of rabbits with spontaneous aortic plaques.

CONCLUSIONS AND IMPLICATIONS

Our animal model induced a severe inflammatory cachexia, comparable to that of persistently active rheumatoid arthritis. The inhibition of COX-2 by celecoxib improves this state, suggesting that COX products play an important role in its development, without affecting the development or the progression of vascular lesions. Overall, these results suggest that celecoxib might be considered as a new therapeutic tool for the treatment of rheumatoid cachexia.     

The outcome of peripartum cardiac failure in Zaria, Nigeria

We have studied 227 women who had peripartum cardiac failure (PPCF) in Zaria, Nigeria, since 1969-72. This follow-up and review of survivors in 1993-95 depended chiefly on a Zaria woman (A. Abdullahi) and on her careful reporting. Overall, 31 (13.7%) were completely lost to follow- up, 17 (7.5%) were thought to be alive, and there were data on 179 others (78.8%). Of the 75 known deaths, 55 were cardiovascular--20 due to PPCF, 31 due to cardiac failure unrelated to pregnancy (CF), and four were due to a cerebrovascular accident. PPCF recurred in 13% of 551 subsequent pregnancies. Thirty-two women had a recurrence of PPCF only, and 27 an episode of CF only. Blood pressures rose steadily over the years. An enlarged left ventricle on discharge after the index admission predicted a poor prognosis. In 1993-5, we compared 100 survivors with 100 non-PPCF controls: 96 PPCF women but only 50 control women took extra salt (p = 0.0001). Significantly more PPCF women than controls had a diastolic pressure of 110 mm Hg (p = 0.011). The syndrome is probably provoked in potentially hypertensive women by the traditional practices of eating kanwa, which is rich in Na+, taking additional excess salt and heating the body after delivery. Evidence is presented that PPCF women are potentially hypertensive, and cannot handle the excess ingested sodium which therefore leads to hypervolaemia and thus PPCF.      

Cochlear otosclerosis (otospongiosis): CT analysis with audiometric correlation

Ninety patients who had suspected or confirmed fenestral or cochlear otosclerosis underwent CT examination. Foci of demineralization in the otic capsule were discovered in 20 ears (12 patients). Audiometric studies of the 12 patients revealed sensorineural hearing loss (SNHL) with distinct correlation of CT findings with progressivity and with involvement of the frequency level subtended by the specific area of the cochlea involved. Foci of abnormal increased density, presumably representing the healed phase of this disorder, were found less frequently than expected. There was a predilection for the basilar turn. All patients had static SNHL in the higher frequencies. The healed phase of this disorder is probably not consistently diagnosable with CT.     

Sensitive detection of human papillomavirus type 16 E7-specific T cells by ELISPOT after multiple in vitro stimulations of CD8+ T cells with peptide-pulsed autologous dendritic cells

Background  

Cervical cancer is the second most common gynecological cancer amongst women world-wide. Despite optimized protocols, standard treatments still face several disadvantages. Therefore, research aims at the development of immune-based strategies using tumor antigen-loaded dendritic cells for the induction of cellular anti-tumor immunity.     

The Feasibility of Early Second Trimester Pregnancy (12 to 14 weeks) Termination with Single Intra-Amniotic Injection of 15-Methyl PGF2α

Summary: Prostaglandin analogues have proven to be safe and effective for second trimester pregnancy terminations when given by various routes. Of these, the intra-amniotic (IA) route has proven to be safer, especially in women with medical disorders, as it causes the least occurrence of systemic side-effects. Previously, blind transabdominal IA instillation of the analogue 15-methyl PGF₂a was routinely possible only after 16 weeks' gestation. With the advent of ultrasound-guided techniques, it has now become possible to use the IA route for very early second trimester pregnancies. This study examines the use of single 1.5 mg 15-methyl PGF₂a IA injection for termination of 12–14 weeks pregnancies. Single injection resulted in successful abortion in 76.5% of women and, in the unsuccessful cases, additional prostaglandin injection resulted in successful abortion in all women within 48 hours without problems. It is therefore feasible to use ultrasound-guided IA prostaglandin injection for successful termination of early second trimester pregnancies.     

Qualitative Phytochemical Screening and In Vitro Antimicrobial Effects of Methanol Stem Bark Extract of Ficus Thonningii (Moraceae)

The methanolic stem bark extract of Ficus thonningii (Moraceae) was subjected to preliminary phytochemical screening and in vitro antimicrobial tests. The phytochemical tests was carried out using standard methods of analysis and these investigations revealed the presence of alkaloids, anthraquinones, carbohydrates, flavonoids, saponins and tannins. The antimicrobial activity of the plant extract was assayed using the agar plate disc diffusion and nutrient broth dilution techniques. Test micro organisms were: Escherichia coli, Klebsiella spp, Pseudomonas aeruginosa, Salmonella typhi (Gram-negative), Staphylococcus aureus and Streptococcus spp. (Gram-positive). The extracts inhibited the growth of all the test organisms at different concentrations especially against Pseudomonas aeruginosa and Streptococcus spp. which had mean inhibition zone of 33.33±7.33 mm and 32.33±2.51 mm respectively. The results showed the MIC of 10 mg ml⁻¹ against pseudomonas and 1.25 against remaining organisms tested. The MBC against Staphylococcus aureus was 2.5 mg ml⁻¹ and that of Streptococcus spp. was found to be 0.625mg ml⁻¹. The extracts showed varied inhibitory activity against the organisms studied.     

In vivo pharmacological interactions between a type II positive allosteric modulator of α7 nicotinic ACh receptors and nicotinic agonists in a murine tonic pain model

Background and Purpose

The α7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that α7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the α7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II α7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model.

Experimental Approach

We assessed the effects of PNU-120596 and choline and the nature of their interactions in the formalin test using an isobolographic analysis. In addition, we evaluated the interaction of PNU-120596 with PHA-54613, an exogenous selective α7 nAChR agonist, in the formalin test. Finally, we assessed the interaction between PNU-120596 and nicotine using acute thermal pain, locomotor activity, body temperature and convulsing activity tests in mice.

Key Results

We found that PNU-120596 dose-dependently attenuated nociceptive behaviour in the formalin test after systemic administration in mice. In addition, mixtures of PNU-120596 and choline synergistically reduced formalin-induced pain. PNU-120596 enhanced the effects of nicotine and α7 agonist PHA-543613 in the same test. In contrast, PNU-120596 failed to enhance nicotine-induced convulsions, hypomotility and antinociception in acute pain models. Surprisingly, it enhanced nicotine-induced hypothermia via activation of α7 nAChRs.

Conclusions and Implications

Our results demonstrate that type II α7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous α7 agonist choline.     

经冠状动脉造影证实的初次冠状动脉支架内血栓形成长期临床预后:431例临床分析

<正>本研究(Dutch Stent Thrombosis Registry)为一项多中心研究,纳入了2004年1月至2007年2月期间经造影确认的ST病例。本研究ST的定义根据ARC分类为明确的血栓形成。根据事件发生的时间分为急性(24 h之内)、亚急性(24h～30 d)、晚期(30 d～1年)和极晚期(1年以后)血栓形成。临床随访采用电话方式询问患者、亲属及家庭医生,或从药房、医院记录获得患者情况。随访内容为主要不良心血管事件(MACE)的发生率(包括死亡、再发ST、心肌梗死和冠状动脉重建术)。研究的一级终点为心源性死亡和明确的再发ST(ARC分类);二级终点为全因死亡、心源性死亡、再发明确的ST、再发明确的或可能的ST、靶血管或非靶血管相关的心肌梗死和任何缺血驱使的靶血管血运重建。共437例患者有明确ST纳入本研究。其中6例因既往曾有ST而被剔除。第1次发生明确ST的431例患者中,140例为急性ST[占总数的32.5%,占金属裸支架(BMS)的33%,占药物洗脱支架(DES)的30%],177例为亚急性ST(占总数