Nicotinic receptor-based therapeutics and candidates for smoking cessation

Tobacco dependence is the most preventable cause of death and is a chronic, relapsing disorder in which compulsive tobacco use persists despite known negative health consequences. All currently available cessation agents (nicotine, varenicline and bupropion) have limited efficacy and are associated with high relapse rates, revealing a need for more efficacious, alternative pharmacotherapies. The major alkaloid in tobacco, nicotine, activates nicotinic receptors (nAChRs) which increase brain extracellular dopamine producing nicotine reward leading to addiction. nAChRs are located primarily presynaptically and modulate synaptic activity by regulating neurotransmitter release. Subtype-selective nAChR antagonists that block reward-relevant mesocorticolimbic and nigrostriatal dopamine release induced by nicotine may offer advantages over current therapies. An innovative approach is to provide pharmacotherapies which are antagonists at nAChR subtypes mediating nicotine evoked dopamine release. In addition, providing multiple medications with a wider array of targets and mechanisms should provide more treatment options for individuals who are not responsive to the currently available pharmacotherapies. This review summarizes the currently available smoking cessation therapies and discusses emerging potential therapeutic approaches employing pharmacological agents which act as antagonists at nicotinic receptors.     

Coronary Angioplasty in Low Risk Patients with Low Dose Heparin and Immediate Withdrawal of the Femoral Sheath

This study reports our preliminary experience of percutaneous coronary angioplasty with low dose heparin and immediate withdrawal of the femoral sheath. After selection, 120 patients underwent a procedure with a low dose of heparin (4,300 ± 700 IU). A total of 120 of 123 lesions (97.6%) were treated successfully by the femoral route. There were no major cardiac complications during the procedure and hospital stay. Patients were allowed to be ambulant 6 hours after the procedure. No significant bleeding occurred. There was no need for surgery relative to the approach route nor for blood transfusion. The use of low dose heparin and immediate withdrawal of the femoral sheath did not increase the risk of coronary angioplasty in these selected patients. The period of bed confinement was shortened and the patients were ambulant earlier, leading to a reduction in their hospital stay with no increase in costs.     

贯叶金丝桃愈伤组织的诱导及其有效成分的定性

目的 :诱导出贯叶金丝桃的愈伤组织 ,并确定其中含有金丝桃素。方法 :在不同条件下采用组织培养技术 ,进行贯叶金丝桃的愈伤组织诱导研究 ,用HPLC方法确定其中含有的金丝桃素。结果和结论 :最佳诱导条件是MS基本培养基加入生长调节物质 2 ,4 D(4μg·L- 1 )和 6 BA(0 .2 μg·L- 1 )。叶腋等分生组织较多的部位易于诱导愈伤组织。诱导出的愈伤组织 ,经HPLC方法确定其含金丝桃素     

IL－2对NOD鼠糖尿病的影响

ＮＯＤ鼠是人类胰岛素依赖型糖尿病的动物模型，其发病与自身免疫有关。环磷酰胺（ＣＰ）可以加速这一过程，使ＮＯＤ鼠糖尿病的发病率提高或提前。一些研究表明：ＮＯＤ鼠的淋巴细胞在淋巴细胞混合反应中（ＭＬＲ），在有或无刺激物的存在下，白细胞介素２（ＩＬ－２）的产量均明显低于正常鼠的淋巴细胞。该实验对注射了一次大剂量的ＣＰ（３００ｍｇ／ｋｇ体重）后的ＮＯＤ鼠试用了ＩＬ－２治疗。结果显示：对于年幼的ＮＯＤ鼠ＩＬ－２治疗１４无可以明显减轻注射ＣＰ后的胰岛破坏加速。病理检查显示三组胰岛炎严重程度积分分别为２９；８１；８８。ＩＬ－２处理组明显低于ＣｏｎＡ处理组与对照组。这个研究还显示，对于１２周龄的ＮＯＤ鼠，经１４天的ＩＬ－２治疗，可以完全预防ＣＰ诱导的糖尿病的发生。糖尿病发病率在ＩＬ－２组为０／１２；对照组为７／１２。但对已发病的ＮＯＤ鼠自发性糖尿病ＩＬ－２不能使其缓解。     

Do men undergoing sterilizing cancer treatments have a fertile future?

This study was designed to assess the effect of cancer treatments on the natural and assisted reproductive potential of men. A cohort of men with cancer, in whom radiotherapy and/or chemotherapy was planned, were invited to participate. Twenty-two pre- and post-treatment semen samples were analysed. The reproductive potential of participants was assessed with respect to the current range of fertility treatment options available. Abnormal sperm concentrations were found in 27% of patients pre-treatment compared to 68% post-treatment following a mean latency of 20 months from treatment. Fifty-nine percent of patients experienced a clinically significant decrease in sperm, concentration following radiotherapy and/or chemotherapy; 23% developed azoospermia following treatment. Eighty-two percent of patients with testicular malignancy had oligo- or azoospermia post-treatment. Only one patient had a clinically significant reduction in the percentage of motile spermatozoa post-treatment. Cryopreservation of semen prior to treatment improved the fertility prospects of 55% of patients. Intracytoplasmic sperm injection (ICSI) enhanced the fertility prospects of a further 14%. In the absence of, or after depletion of, cryopreserved semen, ICSI could enhance the fertility prospects of 45% of patients. Fertilization has been achieved by ICSI using spermatozoa retrieved by testicular biopsy from an azoospermic testicular cancer survivor 8 years after chemotherapy. It was concluded that chemotherapy and/or radiotherapy may depress semen concentration to the extent of rendering a man infertile. The severity of the reduction in sperm concentration following treatment is unpredictable but likely to be most severe in those with testicular malignancy and those treated with radiotherapy or alkylating chemotherapy agents. Not all men are keen to undergo an appraisal of their post-treatment fertility potential, for reasons which are unclear. Improving awareness and education of patients concerning the effects of both cancer and cancer treatments on reproductive potential is essential. With the advent of ICSI, it is possible to offer a very reasonable chance of conception in all men with cancer who present for cryopreservation of semen prior to treatment in whom spermatozoa (even in very low concentrations) are present in the ejaculate.      

The probability that similar haplotypes are identical by descent

The logic of gene mapping in highly penetrant diseases is to find the minimal overlap of haplotypes that are identical by descent (IBD). If the pedigree is unknown, identity by descent of haplotype overlap cannot be established with certainty. In many cases, it is intuitively clear that similar haplotypes are indeed IBD. The logical and statistical evaluation of haplotype overlap requires that probabilities of IBD are substantial. It is, therefore, important to estimate these probabilities. In this paper, we derive a recursive formula for the probability of IBD. Simulations are used to validate the expected values and to study the variability around the expected value. We demonstrate that for populations 1000 generations of age – without bottlenecks – haplotypes of 1 cM consisting of at least five microsatellite markers have a significant probability to be IBD. Likewise, SNP haplotypes of 1 cM should consist of at least nine identical SNP alleles for a similar probability of IBD. Without considering bottlenecks, haplotypes consisting of as few as three SNPs spanning a region of less than 0.01 cM are likely IBD in populations that are 10000 generations of age.     

重症肌无力的外科治疗

目的：探索重症肌无力的外科治疗方法。方法：采用胸腺切除及前纵隔淋巴清扫治疗重症肌无力35例。结果：术后早期死亡1例,34例随访2个月至5年,缓解14例,改善16例,无变化2例,死亡3例。结论;胸腺切除及前纵隔淋巴脂肪清扫治疗重症肌无力效果满意。延迟拔管或早期气管切开术,是防止术后重症肌无力危象的有效措施。胸腺肿瘤已侵及包膜或有局限性恶变的术后放疗可以减少复发,延长了生存时间。     

Cloning and characterization of the guinea pig C5a anaphylatoxin receptor: interspecies diversity among the C5a receptors

The anaphylatoxin C5a receptor (C5aR, CD88 in man) plays a prominent role in mediating inflammatory and host defense processes. Direct evidence of C5aR involvement in host defense mechanisms was demonstrated recently using C5aR knockout mice. Mice deficient in C5aR were unable to clear intrapulmonary-instilled bacteria. The guinea pig system is perhaps unique for exhibiting cross-reactivity with human complement components and its high sensitivity to anaphylatoxins. Therefore, we cloned the guinea pig C5aR from a megakaryocyte cDNA library. The deduced amino acid sequence of guinea pig C5aR is 67% identical to human, 61.6% to dog, 60.2% to mouse and 63.6% to rat C5aR. Transient expression of guinea pig C5aR in COS-7 cells and stable expression on L cell fibroblasts were confirmed by FACS analysis. Competitive binding studies using [125I]C5a and stimulation of calcium mobilization by C5a proved that functional C5aR was expressed on these stably transfected L cells. The N-terminal extracellular region of guinea pig C5aR was five to seven residues shorter than the same region in C5aR from other species and sequence homology was limited to 11%. Other outer membrane loops were also poorly conserved (8-33%) when compared across five species. Transmembrane segments were highly conserved between these various species (46-86%). Guinea pig C5aR binds human C5a, therefore residues critical for C5a binding have been conserved between these species. Sequence comparison of C5aR from multiple species permits conserved elements of the ligand binding sites to be elucidated.