Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states

Familial multiple endocrine neoplasia type 1 (FMEN1) is an autosomal dominant trait characterized by tumors of the parathyroids, gastro- intestinal endocrine tissue, anterior pituitary and other tissues. We recently cloned the MEN1 gene and confirmed its identity by finding mutations in FMEN1. We have now extended our mutation analysis to 34 more unrelated FMEN1 probands and to two related states, sporadic MEN1 and familial hyperparathyroidism. There was a high prevalence of heterozygous germline MEN1 mutations in sporadic MEN1 (8/11 cases) and in FMEN1 (47/50 probands). One case of sporadic MEN1 was proven to be a new MEN1 mutation. Eight different mutations were observed more than once in FMEN1. Forty different mutations (32 FMEN1 and eight sporadic MEN1) were distributed across the MEN1 gene. Most predicted loss of function of the encoded menin protein, supporting the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutation was found in five probands with familial hyperparathyroidism, suggesting that familial hyperparathyroidism often is caused by mutation in another gene or gene(s).      

Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia

A disruption of corticostriatal signaling is believed to underlie the psychotic symptoms of schizophrenia and also contribute to many of the cognitive deficits associated with this disorder. Phosphodiesterase (PDE)10A is a dual substrate PDE highly expressed in striatal medium spiny neurons. Biochemical and behavioral studies indicate that the inhibition of PDE10A enhances striatal output by increasing activity in the cGMP and cAMP signaling pathways. PDE10A inhibitors reduce exploratory activity and antagonize the stimulant response to both amphetamine and N-methyl-d-aspartate antagonists such as phencyclidine. Consistent with their potential as antipsychotic agents, PDE10A inhibitors are potent antagonists of conditioned avoidance responding. The presence of PDE10A in both striatal output pathways may reduce the incidence and severity of dopamine D2 receptor antagonist-like side effects, including extrapyramidal symptoms. In addition, by enhancing corticostriatal signaling, PDE10A inhibitors have the potential to improve some of the cognitive symptoms of schizophrenia.     

Coronary artery anomalies diagnosed by magnetic resonance angiography

Coronary artery anomalies are uncommon entities that may be associated with sudden death. Because of its 2‐D projection imaging nature, conventional X‐ray coronary angiography may not accurately delineate the origins and course of aberrant coronary arteries with respect to the great vessels. Non‐invasive, cross‐sectional imaging techniques such as coronary CT angiography and magnetic resonance angiography are increasingly used in clinical practice to diagnose coronary artery anomalies. Although this study reviews coronary artery anatomy and selected anomalies as seen with true fast imaging with steady‐state precession magnetic resonance angiography, the information provided is equally applicable to electrocardiogram‐gated coronary CT angiography.     

人脐血CD34+ 细胞静脉移植对急性心肌梗死大鼠血流动力学指标和超声心动图指标的影响

目的:观察人脐带血CD34 细胞移植治疗急性心肌梗死大鼠的可行性及其对心功能的影响。方法:实验于2006-03/10在首都医科大学附属北京友谊医院完成。①选取11～13周龄雄性SD大鼠40只,随机数字表法分为假手术组10只、模型对照组15只、细胞移植组15只。脐血由北京市脐血干细胞库提供,采自无妊娠并发症、身体健康、新生儿足月分娩(37～40周)孕妇,均签署知情同意书,自愿捐献用于科学研究和临床治疗。②一次性血袋抽取孕妇脐带血80～120mL,按5∶1比例加入60g/L羟乙基淀粉,4℃420r/min离心8min;去除红细胞,留取上层含有核细胞的血浆层,4℃1180r/min离心10min,去除血浆,留取有核细胞,测CD34 含量为0.35%～0.42%。③模型对照组、细胞移植组大鼠建立急性心肌梗死模型,麻醉后切开第4、5肋间肌,暴露心脏,在动脉圆锥和左心耳间、距左心耳下1mm处(相当于左前降支近段)用Prolene线结扎。假手术组只挂线不结扎。根据左室前壁颜色变白、活动减弱和心电图ST段明显抬高作为急性心肌梗死模型成功标志。④术后3h内,细胞移植组经尾静脉注射0.5mL人脐血干细胞悬液(含干细胞2×1010L-1),模型对照组经尾静脉注射0.5mL生理盐水。饲养30d。⑤分别于术前、术后1d和术后30d进行超声心动图检测。并于术后30d进行血流动力学检测。结果:假手术组挂线过程中死亡1只,模型对照组造模及细胞移植过程死亡4只,细胞移植组造模及细胞移植过程死亡5只。①人脐血CD34 细胞移植30d后对大鼠血流动力学的影响:与假手术组比较,模型对照组左室收缩压、左室压力最大变化率均明显减小(t=2.16～5.14,P均<0.05),左室舒张末压、心率均明显增加(t=2.01～8.86,P<0.01或0.05);与模型对照组比较,细胞移植组左室收缩压、左室压力最大变化率均明显增加(t=2.72～2.35,P均<0.05),左室舒张末压明显减小(t=4.24,P<0.01),心率无明显变化(t=1.67,P>0.05)。②人脐血CD34 细胞移植前后超声心动图检查结果:与假手术组比较,术前模型对照组和细胞移植组各指标无明显变化;术后1,30d模型对照组和细胞移植组左室舒张末期内径、左室收缩末期内径、左室舒张末容积、左室收缩末容积均明显增加(t=2.14～9.98,P<0.05或0.01),左室前壁厚度、左室后壁厚度、左室射血分数、左室短轴缩短率均明显减小(t=2.52～14.23,P<0.05或0.01)。与模型对照组比较,术前和术后1d细胞移植组各指标无明显变化,但术后30d左室舒张末期内径、左室收缩末期内径、左室舒张末容积、左室收缩末容积均明显减小(t=2.07～7.04,P<0.05或0.01),左室前壁厚度、左室后壁厚度、左室射血分数、左室短轴缩短率均明显增加(t=3.22～9.85,P均<0.01)。结论:在未使用免疫抑制剂的情况下,人脐带血CD34 细胞静脉移植可明显改善急性心肌梗死大鼠各项心功能指标,未见明显不良反应。     

Structural basis for the catalytic mechanism of human phosphodiesterase 9

The phosphodiesterases (PDEs) are metal ion-dependent enzymes that regulate cellular signaling by metabolic inactivation of the ubiquitous second messengers cAMP and cGMP. In this role, the PDEs are involved in many biological and metabolic processes and are proven targets of successful drugs for the treatments of a wide range of diseases. However, because of the rapidity of the hydrolysis reaction, an experimental knowledge of the enzymatic mechanisms of the PDEs at the atomic level is still lacking. Here, we report the structures of reaction intermediates accumulated at the reaction steady state in PDE9/crystal and preserved by freeze-trapping. These structures reveal the catalytic process of a PDE and explain the substrate specificity of PDE9 in an actual reaction and the cation requirements of PDEs in general.     

High prevalence of vitamin D deficiency in elderly patients with advanced osteoarthritis scheduled for total knee replacement associated with poorer preoperative functional state

Vitamin D deficiency has been reported previously in patients with osteoarthritis undergoing total hip arthroplasty. We found a high prevalence of vitamin D deficiency in elderly patients with advanced knee osteoarthritis scheduled for total knee replacement and also a significant association with a lower preoperative functional state. A review of the literature is given on vitamin D deficiency in patients with knee osteoarthritis and the association with lower outcome scores after arthroplasty is discussed.     

Can the Ottawa and Pittsburgh rules reduce requests for radiography in patients referred to acute knee clinics?

Our aim was to study the role of the Ottawa and Pittsburgh rules to reduce the unnecessary use of radiographs following knee injury. We prospectively reviewed 106 patients who were referred to our clinic over a 3-month period. The Ottawa and Pittsburgh rules were applied to individual patients to evaluate the need for radiography. One hundred and one patients (95%) had radiography of their knee. Five patients (5%) had a fracture of their knee and in all cases, the Ottawa and Pittsburgh knee rules were fulfilled. Using the Ottawa rules, 27 radiographs (25%) could have been avoided without missing a fracture. Using the Pittsburgh rules, 32 radiographs (30%) could have been avoided. The Ottawa and Pittsburgh rules have a high sensitivity for the detection of knee fractures. Their use can aid efficient clinical evaluation without adverse clinical outcome and may reduce healthcare costs.     

Phosphodiesterase 10 inhibition reduces striatal excitotoxicity in the quinolinic acid model of Huntington's disease

Decreased activity of cAMP responsive element-binding protein (CREB) is thought to contribute to the death of striatal medium spiny neurons in Huntington's disease (HD). Therefore, therapies that increase levels of activated CREB, may be effective in fighting neurodegeneration in HD. In this study, we sought to determine whether the phosphodiesterase type 10 (PDE10A) inhibitor TP10 exerts a neuroprotective effect in an excitotoxic model of HD. Rats were surgically administered with quinolinic acid into striatum and subsequently treated with TP10 daily for two or eight weeks. After 2 weeks of TP10 treatment, striatal lesion size was 52% smaller and the surviving cell number was several times higher than in the vehicle-treated group. These beneficial effects of TP10 were maintained through 8 weeks. TP10 treatment also increased significantly the levels of activated CREB in the striatal spiny neurons, which is hypothesized to be a contributing mechanism for the neuroprotective effect. Our findings suggest PDE10A inhibition as a novel neuroprotective approach to the treatment of HD and confirm the importance of phosphodiesterase inhibition in fighting the disease.