Neurokinin A as a potent bronchoconstrictor

Neurokinin A (NKA) and B (NKB) were more potent bronchoconstrictive agents than substance P (SP) in guinea pig tracheal strips. The content of NKA in guinea pig lung homogenate was 2.26 +/- 1.09 pmol/g wet lung, which was approximately half that of SP (4.46 +/- 1.33 pmol/g wet lung); NKB was not detected in the guinea pig lung homogenate (less than 0.01 pmol/g wet lung). Histologically, NKA-immunoreactive fibers were distributed in the bronchial smooth muscle layers. Pulmonary arteries and veins were also found to be innervated by NKA-immunoreactive nerves. In addition, a few fibers were observed in the trachea, bronchioles, and alveoli. These findings suggest that NKA may be one of the neurotransmitters of the noncholinergic bronchoconstrictive nerves.     

One in five subjects with normal thyroid ultrasonography has altered thyroid tests

The relation between thyroid ultrasonography and laboratory, and the relationship of thyroid volume with clinical and anthropometric parameters, are not well clarified. Aim of the study was to investigate normal and hypoechoic-inhomogeneous not nodular thyroid gland in predicting thyroid tests, and to assess the correlation of thyroid volume with several clinical parameters. The series included 434 subjects (244 with normal thyroid ultrasonography, and 190 with hypoechoic-inhomogeneous thyroid) at their first evaluation. Subjects with normal ultrasonography and skewed tests were re-evaluated after one year. All subjects with normal ultrasound showed normal free-T?, while TSH was elevated in 9.8% of cases and thyroid antibodies were positive in another 9.8%. In patients with hypoechoic-inhomogeneous thyroid, free-T? was low in 33.2%, TSH was elevated in 78.4% and thyroid antibodies were positive in 76.3%. Normal ultrasonography matched with normal tests in 81.1% of cases while hypoechoic-inhomogeneous thyroid in 9.5% (p<0.001). The re-evaluation of tests showed no significant difference. In subjects with both normal ultrasonography and tests, thyroid volume was correlated with age (p=0.001), weight (p=0.003), BMI (p=0.04), body surface area (p=0.002). Thyroid laboratory assessment was different between subjects with ultrasonographically normal or hypoechoic-inhomogeneous thyroid. Thyroid volume of thyroid diseases-free subjects was correlated with age, weight, BMI and body surface area, and this should be of interest to investigate the references of normality of thyroid size.     

N-acetyl serotonin derivatives as potent neuroprotectants for retinas

N-acetylserotonin (NAS) is synthesized from serotonin by arylalkylamine N-acetyltransferase (AANAT), which is predominantly expressed in the pineal gland and retina. NAS activates TrkB in a circadian manner and exhibits antidepressant effects in a TrkB-dependent manner. It also enhances neurogenesis in hippocampus in sleep-deprived mice. Here we report the identification of NAS derivatives that possess much more robust neurotrophic effects with improved pharmacokinetic profiles. The compound N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) selectively activates TrkB receptor with greater potency than NAS. It potently protects retinas from light-induced retinal degeneration (LIRD), which is tightly coupled with pronounced TrkB activation in retinas. Pharmacokinetic studies demonstrate that this compound is stable in serum and liver microsomes. It can pass the blood-brain barrier and blood-retinal barrier. Hence, HIOC is a good lead compound for further drug development for treating retinal degenerative diseases.     

PRL as a novel potent cofactor for platelet aggregation.

Pregnancy (including puerperium) is a period of hypercoagulability and seems to be an independent major risk factor for venous thromboembolism (VTE). However, the basis of the increased risk of VTE in pregnancy and around delivery is unknown. We hypothesized that changes in PRL, which is a prominently increased hormone during pregnancy and lactation, might be involved in the activation of platelets. To investigate platelet functional abnormalities in pregnancy, we assessed the ADP-stimulated and nonstimulated P-selectin expression of platelets in 42 consecutive pregnant women, 22 normo- and hyperprolactinemic patients with pituitary tumors, and controls. In addition, the aggregation of platelets by human PRL in vitro was studied. We found a significant correlation between PRL values and ADP stimulation of platelets in pregnant women (r = 0.56; P < 0.0001) and patients with pituitary tumors (r = 0.57; P = 0.006). Hyperprolactinemic pregnant women or hyperprolactinemic patients with pituitary tumors revealed significantly higher ADP stimulation of platelets (P < 0.0001) than healthy controls or normoprolactinemic patients with pituitary tumors. These results were reconciled by increased in vitro stimulation and aggregation of platelets using human PRL. Our novel findings demonstrate that hyperprolactinemia causes increased platelet aggregation via ADP stimulation both in vitro and in vivo. Moreover, our data indicate that PRL may be a physiological cofactor of the delicate coagulation balance during pregnancy and puerperium that might explain the increased risk of VTE in pregnant women around delivery. Further studies of the interaction between PRL and platelets will clarify the clinical relevance of hyperprolactinemia as a potential risk factor for VTE.     

Identification of simple arylfluorosulfates as potent agents against resistant bacteria

Sulfur fluoride exchange (SuFEx), a next generation of click chemistry, opens an avenue for drug discovery. We report here the discovery and structure–activity relationship studies of a series of arylfluorosulfates, synthesized via SuFEx, as antibacterial agents. Arylfluorosulfates 3, 81, and 101 showed potency to overcome multidrug resistance and were not susceptible to the generation of resistance. They exhibited rapid bactericidal potency and selectively killed gram-positive bacterial strains. These compounds also exhibited the ability to disrupt established bacterial biofilm and kill persisters derived from biofilm. Furthermore, arylfluorosulfate 3 had a synergistic effect with streptomycin and gentamicin. In addition, their anti-MRSA potency was evaluated and determined by the Caenorhabditis elegans model.

Antibiotic resistance is a tremendous threat to global health. Some of the most concerning multidrug-resistant pathogen strains include methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA, respectively), vancomycin-resistant Enterococcus faecium (VRE), Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp (1–3). Antibiotic resistance is one of the biggest public health challenges and is a leading cause of death with at least 2.8 million infected cases and more than 35,000 deaths every year in the United States (4). Therefore, the development of novel antibacterial drugs with the ability to overcome drug-resistance is urgently needed. Furthermore, our general understanding of the role of our microbiomes (i.e., skin, oral, gut, etc.) in antibiotic resistance and responses is ever increasing (5–7). The next generation of antibacterial agents will require limited drug promiscuity to eliminate resistance and decrease unwanted off-target effects on our symbiotic commensal organisms and immunity (8, 9).Sulfur fluoride exchange (SuFEx) (10), a new generation of click chemistry, has found diverse applications to chemical synthesis (11–16), materials science (17–22), chemical biology (23–28), and drug discovery (29, 30). In our previous studies, we demonstrated that SuFEx modification is a highly reliable approach for the late-stage functionalization of drugs and drug-like molecules to generate new compounds with improved properties (31, 32). Later on, Ravindar et al. reported the synthesis of arylfluorosulfate analogs and screened them for antimicrobial activity (33).Here we report further screening studies on arylfluorosulfate derivatives (Ar-O-SO₂-F) in our laboratory and have found several simple molecules which are potent against methicillin- and vancomycin-resistant strains (Fig. 1 and SI Appendix, Figs. S1 and S2). Through structure and activity relationship (SAR) studies, we determined that the -OSO₂F moiety is essential for these compounds’ antibacterial activities. Not only are they capable of inhibiting bacterial biofilm formation, but they are also able to disrupt established bacterial biofilm and induce the killing of persister cells. Significantly, these arylfluorosulfates are effective against MRSA infection in a Caenorhabditis elegans-based infection model. Our findings reported here thus may serve as the foundation toward the development of arylfluorosulfate-based antibacterial agents.Open in a separate windowFig. 1.(A) Arylfluorosulfates were derived from phenols or phenol’s precursors. (B) The structures of antibacterial arylfluorosulfates 3, 81, and 101 and their MIC values against MRSA.     

脂质沉积性肌病误诊为多肌炎一例

患者 ,女性 ,2 1岁。因下肢肌无力伴双大腿肌肉酸痛 3个月于 1999年 10月 2 9日就诊我院门诊。 3个月前无诱因出现下肢肌无力 ,下蹲后起立困难 ,步行约 10ｍ即感不适 ,症状渐加重 ,伴心悸、胸闷 ,无晨轻夜重现象。无抬头、举臂困难或吞咽困难。查体 :生命体征稳定。神清 ,发育、步态正常 ,活动乏力。无皮疹。心肺无异常。肝脾无肿大。双下肢近端肌肉压痛 ,上肢肌力正常 ,下肢肌力 4级 ,腱反射迟钝 ,深、浅感觉正常 ,病理征阴性。查ＣＰＫ 10 84ＩＵ/Ｌ。胸片、心电图正常。以“多肌炎”收住入院。ＷＢＣ 6.9× 10 9/Ｌ ,Ｈｂ 10 2ｇ/Ｌ。抗…     

肝包囊虫病误诊为肝癌一例

患者 ,男 ,2 1岁 ,学生 ,四川达州市人。因上腹不规则疼痛 1年 ,剑突下剧痛 4天 ,入住我院。既往无肝病史 ,无牛羊接触史。查体 :Ｔ 37.1℃ ,Ｐ 80次 /分 ,Ｒ 2 0次 /分 ,ＢＰ 12 / 8ｋＰａ ,神清 ,消瘦 ,无黄疸 ,左锁骨上淋巴结未触及 ,心肺正常 ,腹平软 ,肝肋下未触及 ,剑突下 8ｃｍ ,边钝触痛 ,表面光滑 ,质硬 ,脾肋下 3ｃｍ。移浊 (-)。辅助检查 :血常规、肝功、二对半、肾功均正常。Ｂ超提示肝左叶增大 ,形态失常 ,其内可见 6.7ｃｍ× 5 .7ｃｍ的实质性团块 ,边界不规整 ,内回声不均 ,呈强弱相等 ,并可见“结中结”及声晕征象 ,在此团…     

恶性疟疾误诊为AIDS一例

1 病例报告 患者,男,30岁,因发热、乏力、纳差、呕吐、尿黄、咳嗽30余天于2009年6月11日入院。患者30多天前出现持续性发热,体温最高达40．0℃,发热时口渴、气短、头痛、全身肌肉酸痛,无寒战。因使用解热镇痛药,故热型不典型。患者乏力、纳差、厌油、恶心,呕吐胃内容物数次,尿色深黄,咳白色泡沫痰少许。外院诊断为AIDS,给予静脉滴注“氨苄西林＋舒巴坦”,症状无缓解。     

甲状旁腺机能亢进误诊为类风湿性关节炎一例

患者,女性,12岁.因腰及双膝髋关节疼痛伴活动障碍8个月入院.患者8月前出现双膝关节疼痛,继而双髋、双踝关节及腰部疼痛.在一次打乒乓球后,出现腰部不能直立,并逐渐出现步态异常,行走时两小腿外翻,呈X型,此时其他关节疼痛反而缓解.     

Recombinant human CD19-ligand protein as a potent anti-leukaemic agent

We report the cloning and characterization of a novel 54-kDa high-mobility group (HMG)-box protein as the ligand for the human pan-B cell co-receptor CD19 (CD19-L), which interacts with the extracellular domain of CD19 in trans. CD19-L is the first CD19-specific recombinant human protein with potent anti-leukaemic activity against B-lineage acute lymphoblastic leukaemia (ALL), the most common form of childhood cancer and the second most common form of acute leukaemia in adults. Soluble recombinant CD19-L protein exhibited exquisite specificity for the extracellular domain of CD19 and strong binding to the surface of B-lineage leukaemia/lymphoma cells. Engagement of CD19 co-receptor on B-lineage ALL cells with CD19-L perturbed the CD19-associated signalling network, altering the expression levels of multiple genes directly involved in regulation of apoptosis, and triggered rapid apoptotic cell death in a CD19-specific manner. The identification of human CD19-L may lead to therapeutic innovation for B-lineage ALL and other B-lineage lymphoid malignancies as well as B-cell lymphoproliferative states and systemic autoimmunity.     

Personality disorder features as predictors of symptoms five years post-treatment

Personality disorders are associated with dysfunction in a variety of areas. Recent longitudinal research has shown that personality disorders are also predictive of problems later in life, as well as of poor response to treatment of depression and anxiety. This study assessed whether personality disorder features were associated with psychiatric symptoms in a cohort of women treated for substance abuse in Sweden. Patients were diagnosed with personality disorders using the Structured Clinical Interview for DSM-IV (SCID-II) personality questionnaire and SCID-II interview, and were then administered a self-report questionnaire designed to measure symptoms of psychiatric illness, the Symptoms Checklist-90 (SCL-90), during and five years after treatment. Concurrently, features of all personality disorders, except histrionic, were associated with SCL-90 score. At five-year follow-up, most personality disorders remained associated with SCL-90 score, with the exception of paranoid and schizoid personality disorder. After controlling for baseline score on the SCL-90, conduct disorder, borderline personality disorder, and narcissistic personality disorder remained significantly associated with symptoms at follow-up. After controlling for abstinence and baseline score, only borderline personality disorder features remained associated with SCL-90 score at follow-up. Patients with personality disorders should be monitored after treatment for psychiatric symptoms.     

人骨形态发生蛋白9通过诱导棕色脂肪形成发挥抗肥胖作用

人骨形态发生蛋白9（BMP-9）高度表达于肝脏细胞.胰岛素注射后,可迅速发挥降糖作用,并在2h内作用逐渐减弱;而重组人BMP-9对糖尿病小鼠的最大降糖效果发生在注射后30 h左右.给予BMP-9抗体可诱导大鼠糖耐量异常和胰岛素抵抗的发生.以上研究结果说明BMP-9在葡萄糖稳态调节中起着重要作用,但其作用机制尚不清楚,目前认为BMP-9可能通过调节多种酶的表达参与葡萄糖稳态的调节.     

Functional screening identifies miR-315 as a potent activator of Wingless signaling

The existence of vast regulatory networks mediated by microRNAs (miRNAs) suggests broad potential for miRNA dysfunction to contribute to disease. However, relatively few miRNA-target interactions are likely to make detectable contributions to phenotype, and effective strategies to identify these few interactions are currently wanting. We hypothesized that signaling cascades represent critical points of susceptibility to miRNA dysfunction, and we developed a strategy to test this theory by using quantitative cell-based screens. Here we report a screen for miRNAs that affect the Wingless (Wg) pathway, a conserved pathway that regulates growth and tissue specification. This process identified ectopic miR-315 as a potent and specific activator of Wg signaling, an activity that we corroborated in transgenic animals. This miR-315 activity was mediated by direct inhibition of Axin and Notum, which encode essential, negatively acting components of the Wg pathway. Genetic interaction tests substantiated both of these genes as key functional targets of miR-315. The ability of ectopic miR-315 to activate Wg signaling was not a trivial consequence of predicted miRNA-target relationships because other miRNAs with conserved sites in the Axin 3' UTR neither activated Wg outputs nor inhibited an Axin sensor. In summary, activity-based screening can selectively identify miRNAs whose deregulation can lead to interpretable phenotypic consequences.