Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease

alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.      

Autonomic response to auditory stimulation

Autonomic and behavioral response to fear stimulation (sudden noise 80 dB) was studied in 12 sleeping infants at ages 8–50 weeks. The aim of the present study was to identify a possible passive defense response in infants. The response, which is widespread in birds and mammals, is characterized by apnea and bradycardia with circulatory changes as seen during the forced diving response. Upon stimulation, two respiratory responses were elicited: apnea preceded by irregular respiration or simple irregular respiration. Apnea was elicited in 58% of stimulations at ages 8–16 weeks compared to 14% at 28–50 weeks. The mean duration of apnea decreased from 7.8 s(± 1.8 s) at 8–13 weeks to 4.7s (± 1.1s) at 17–20 weeks. The preceding irregular respiration increased from 5.3 s (± 4.4 s) to 10.6 s (± 5.4 s) at the same ages. The heart rate response was biphasic and were interpreted as the orienting response. The mean deceleration in relation to apnea was 16% at 8–16 weeks and was reduced to 8% at 28–50 weeks. Infants of smoking mothers were more prone to respond with apnea than infants of nonsmoking mothers (73% versus 38%). REM sleep and long postprandial sleep time increased the probability of apnea response (62% versus 38% and 66% versus 35%). The responses seen may be interpreted as expressions of the passive defense response.     

A phase I trial of recombinant human interleukin-11 (neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy

We performed a phase I trial of recombinant human interleukin-11 (rhIL- 11) in women with breast cancer. Cohorts of three to five women were accrued to five dosage levels of rhIL-11 (10, 25, 50, 75, and 100 micrograms/kg/d). rhIL-11 alone was administered by a daily subcutaneous injection for 14 days during a 28-day prechemotherapy "cycle 0." Patients (pts) subsequently received up to four 28-day cycles of cyclophosphamide (1,500 mg/m2) and doxorubicin (60 mg/m2) chemotherapy followed by rhIL-11 at their assigned dose (days 3 through 14). Sixteen pts (13 stage IV, 3 stage IIIB) were accrued to this study. Median age was 53 years and median Eastern Cooperative Oncology Group Performance Status was 0. A grade 3 neurologic event was seen in 1 pt at 100 micrograms/kg. Because of the degree of grade 2 constitutional symptoms (myalgias/arthralgias and fatigue) at 75 micrograms/kg, dose escalation was stopped and 75 micrograms/kg was the maximally tolerated dose. No other grade 3 or 4 adverse events related to rhIL-11 were seen. The administration of rhIL-11 was not associated with fever. Reversible grade 2 fatigue and myalgias/arthralgias were seen in all pts at 75 micrograms/kg. Weight gain of 3% to 5% associated with edema was seen at doses > 10 micrograms/kg but a capillary leak syndrome was not seen. rhIL-11 alone was associated with a mean 76%, 93%, 108%, and 185% increase in platelet counts at doses of 10, 25, 50, and 75 micrograms/kg, respectively. No significant changes in leukocytes were seen. A mean 19% decrease in hematocrit was observed. Acute-phase proteins increased with treatment at all doses. Compared with patients at the 10 micrograms/kg dose, patients receiving doses > or = 25 micrograms/kg experienced less thrombocytopenia in the first two cycles of chemotherapy. We conclude that rhIL-11 has thrombopoietic activity at all doses studied, is well tolerated at doses of 10, 25, and 50 micrograms/kg, and at doses > or = 25 micrograms/kg has the potential to reduce chemotherapy-induced thrombocytopenia in this model.     

Long-term Surgical Outcomes for Vertical Deviations in Thyroid Eye Disease

Introduction: Vertical deviations in thyroid eye disease (TED) can present a surgical challenge due to the difficulty and unpredictability of surgery and the high risk of postoperative drift towards overcorrection. This study reports the postoperative outcomes of patients who underwent adjustable vertical strabismus surgery with Vicryl sutures for thyroid eye disease. Methods: We reviewed the records of patients seen for vertical TED strabismus surgery from January 2005 through December 2009. Clinical details were recorded preoperatively, post-adjustment, and at 3 weeks, 3 months, and 1 year postoperatively. Results: The study included 42 patients. Mean age was 62.4 years and 70% were female. All patients were diplopic preoperatively. The mean near vertical deviation was 21.1 prism diopters (PD) preoperatively, 4.0 PD at 3 weeks postoperatively, 5.0 PD at 3 months, and 4.4 PD at 1 year (all mean results representing undercorrection). 71.4% were free of diplopia postoperatively. Seven patients required further surgery, 2 patients needed further botulinum toxin A. Eight patients experienced an overcorrection; five at 3 weeks, seven at 3 months, and eight at 1 year. There was a significant difference in the mean near angle at tie-off post-adjustment in the patients that overcorrected compared to those that did not reverse (3.1 PD vs 7.1 PD; P=0.005). Discussion: Adjustable surgery for vertical strabismus in thyroid eye disease may result in late overcorrection and the need for further intervention. We propose that aiming for an immediate post-adjustment angle of 8 PD undercorrection for near would allow for postoperative drift and reduce the chances of a late overcorrection. This would require careful preoperative counseling of the patient in order to explain that immediate undercorrection and persistent diplopia were necessary in order to generate a better long-term result.     

Segond tibial condyle fracture: lateral capsular ligament avulsion

Avulsion fractures in the appendicular skeleton are a result of stress on a specific structure that is firmly attached to bone. A small avulsion fracture from the directly lateral surface of the lateral tibial condyle results from excessive tension on the lateral capsular ligament of the knee joint. Recognition of this fracture on an anteroposterior radiograph of a traumatized knee represents substantial evidence of major injury to the lateral joint capsule. This fracture also has a strong association with rupture of the anterior cruciate ligament. The avulsed tibial fragment is remarkably constant in site and appearance. The typical fragment is isolated by a longitudinal fracture line separating a small piece of bone from the lateral tibia. It is elliptical in outline (10 X 3 mm), with its proximal border lying 4 mm distal to the subarticular cortex of the lateral tibial condyle. A hemarthrosis of the knee joint is consistently visible.     

The presence of chorionic gonadotrophin beta subunit in normal cyclic human endometrium

The aim of the present study was to determine whether human endometrial cells are able to secrete beta-chorionic gonadotrophin (betaCG). Immunohistochemical studies and in-situ hybridization were performed in order to provide evidence for the occurrence of betaCG in the normal endometrium in 15 patients in the proliferative phase, two patients in the periovulatory phase and 13 patients in the secretory phase. Neither immunohistochemical nor hybridization reactions could be recognized during the proliferative phase. In contrast, both protein and betaCG mRNA were observed in the glandular cells of the endometrium during the secretory phase. The results were supported by Western blotting of secretory phase endometrium extracts and the assessment of the functional secretory capacity of primary endometrium cultures. In comparison with cultured and separated cell fractions, tissue extracts showed a higher betaCG, indicating a regulatory interaction. In conclusion, betaCG can be demonstrated in normal human cyclic endometrium, suggesting a paracrine role in endometrial physiology.      

Combining Viral Vectored and Protein-in-adjuvant Vaccines Against the Blood-stage Malaria Antigen AMA1: Report on a Phase 1a Clinical Trial

The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines—chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising “mixed-modality” regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible.     

电针对单纯性肥胖大鼠下丘脑组织中瘦素和神经肽Y表达的影响

目的:观察电针对单纯性肥胖大鼠下丘脑瘦素和神经肽Y表达的影响,探索电针减肥的机制。方法:实验于2005-12/2006-06在中南大学湘雅医院中西医结合研究所实验室完成。①取1月龄刚断乳SD雄性大鼠,随机取6只饲以普通饲料为正常对照组,其他大鼠饲以高脂饲料,喂养3个月后,选择体质量超过正常对照组20%的单纯性肥胖大鼠12只,随机分为模型组和电针组2组,每组6只。②电针组大鼠电针双侧足三里、天枢、三阴交穴,采用疏密波,电流强度0.3～0.6mA,留针20min,1次/d,共20次;其他2组不电针。实验期间均饲以普通饲料。③观察实验大鼠体质量、体长、Lee's指数及体脂,采用Western-blot技术检测下丘脑组织中瘦素、神经肽Y表达的变化。结果:18只大鼠进入结果分析。①模型组大鼠体质量和Lee’s指数高于正常对照组[(451.8±14.8),(323.6±6.8)g;324.25±1.4,305.14±1.5;P均<0.01];电针组电针后体质量和Lee’s指数低于电针前[(372.2±20.4),(454.7±19.7)g;307.71±1.5,323.56±1.6;P均<0.01]。②模型组大鼠心包、肾周和附睾脂肪量均高于正常对照组(P<0.01);电针组电针后心包、肾周和附睾脂肪量低于电针前(P<0.01)。③模型组下丘脑组织中瘦素蛋白表达低于正常对照组(0.62±0.11,0.88±0.15,P<0.01),电针组高于模型组(0.85±0.13,P<0.01);模型组下丘脑组织中神经肽蛋白表达高于正常对照组(2.42±0.27,1.75±0.24,P<0.01),电针组高于模型组(1.87±0.21,P<0.01)。结论:电针有良好的减肥效果,其作用可能与电针增强下丘脑组织瘦素蛋白的表达、同时抑制下丘脑组织中的神经肽Y蛋白表达有关。