Genetic linkage of the tricho-dento-osseous syndrome to chromosome 17q21

Tricho-dento-osseous syndrome (TDO), MIM# 190320, is transmitted as a highly penetrant autosomal dominant trait that is characterized by variable clinical expression. The principal clinical features include kinky/curly hair in infancy, enamel hypoplasia, taurodontism, as well as increased thickness and density of cranial bones. Possible genetic linkage has been reported for TDO with the ABO blood group locus, but the gene defect remains unknown. We have identified four multiplex families (n = 63, 39 affected, 24 unaffected) from North Carolina segregating TDO. We previously have excluded a major locus for TDO in the ABO region for these families. Utilizing a genome-wide search strategy, we obtained conclusive evidence for linkage of the TDO syndrome locus to markers on chromosome 17q21 (D17S791, Z max = 10.54, Theta = 0.00) with no indication of genetic heterogeneity. Multipoint analysis suggests the TDO locus is located in a 7 cM chromosomal segment flanked by D17S932 and D17S941. This finding represents the first step towards isolation and cloning of the TDO gene. Identification of this gene has important implications for understanding normal and abnormal craniofacial development of hair, teeth and bone.      

Hallucinations, delusions, and cognitive decline in Alzheimer's disease

OBJECTIVES: To examine the occurrence of hallucinations and delusions in Alzheimer's disease over a 4 year period and their association with rate of cognitive decline. METHODS: A cohort of 410 persons with clinically diagnosed Alzheimer's disease underwent annual clinical evaluations over a 4 year period. Participation in follow up exceeded 90% in survivors. Evaluations included structured informant interview, from which the presence or absence of hallucinations and delusions was ascertained, and detailed testing of cognitive function. The primary cognitive outcome measure was a composite cognitive score based on 17 individual performance tests. The mini mental state examination (MMSE) and summary measures of memory, visuoconstruction, repetition, and naming were used in secondary analyses. RESULTS: At baseline, hallucinations (present in 41%) and delusions (present in 55%) were common and associated with lower cognitive function. In analyses that controlled for baseline level of cognitive function, demographic variables, parkinsonism, and use of antipsychotic medications, hallucinations, but not delusions, were associated with more rapid cognitive decline on each cognitive measure. In the primary model, there was a 47% increase in the average annual rate of decline on a composite cognitive measure in those with baseline hallucinations compared with those without them. This effect was mainly due to a subgroup with both auditory and visual hallucinations. CONCLUSION: These findings suggest that the presence of hallucinations is selectively associated with more rapid cognitive decline in Alzheimer's disease.     

004 65岁以上收缩功能正常的心衰者的临床特点

众所周知,充血性心衰(CHF)为老年人较为常见的临床综合征之一.迄今关于左室收缩功能正常的CHF老人的相关临床特点远未清楚,本文特此进行了大样本分析. 对象与方法 4842例老年人,男1922例,女2920例,年龄66～103岁.尔后人均随访1年.旨在分析老年CHF年发病率,以及左室收缩功能正常的CHF老人相关临床特点. 结果随访期内,罹发1次或以上CHF者共425例次(8.8%/年).与未患发CHF老人相比,CHF老人平均年龄更大(79±6岁:77±5岁,P＜0.001),女性居多,尤以高龄女性更多,如85岁以上的高龄女性CHF年发病率约较65～69岁女性高2倍(14%∶6.6%,P＜0.001),AMI史、房颤、高血压、糖尿病、慢性阻塞型肺病、吸烟者均多,血脂及血肌酐亦高.多变量分析表明,罹患CHF与下列因素有关:老年尤其是高龄[年龄每增加5岁的患病奇数率(OR)女性1.2,男性1.1],AMI史(OR7.3),房颤者(OR3.0),糖尿病(OR2.1),肾功能不全(血肌酐≥1.5mg/dl的OR2.0),慢性阻塞肺病(仅老年女性的OR为1.8),以及左房、左室内径增大(内径每递增1cm的OR为2.0),和左室重量增加、左室收缩末期室壁张力增高、早期跨心房血流增多.超声心动图检测结果显示,CHF老人中,左室收缩功能正常者达55%,而仅有左室舒张功能不全,且左室收缩功能正常或轻度减退者高达80%.其中女性左室收缩功能正常者尤较男性多见(67%∶42%,P＜0.001),表现为单纯左室舒张功能不良.而在左室收缩功能正常的CHF老人,常伴有左室内径较小、左室收缩末期室壁张力较低、左室重量较轻、左室收缩末期室壁厚度增加,而左室射血分数正常或仅轻度降低. 讨论以上结果提示,在老年人群中,CHF年发病率相对较高,且随年龄而增加,多数左室收缩功能正常,仅有左室舒张功能障碍,尤其是在高龄女性,亦即高龄女性左室舒张功能不全性CHF更为常见.对此,临床上更应拟出合理的防范措施,来正确诊治老年CHF综合征. (袁志敏摘)     

A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.     

Effects on the buoyant density of rabbit platelets of ADP and agents that increase the concentration of cyclic AMP

Rabbit platelets were aggregated by adenosine diphosphate (ADP), allowed to deaggregate and then separated into density subpopulations by centrifugation through discontinuous Stractan density gradients. Although ADP causes little or no release of the contents of the amine storage granules of rabbit platelets, ADP caused a decrease in platelet density as compared with control platelets subjected to the same procedures except for exposure to ADP. The density change persisted for at least four hours. The apparent size of platelets stimulated with ADP increased initially, but returned to control values during a one-hour period. A similar decrease in platelet density was observed with an albumin density gradient. Under conditions in which aggregation did not occur in response to ADP with ethylenediaminetetraacetic acid (EDTA) in the medium, little or no decrease in platelet density was observed. Agglutination with polylysine did not change platelet density. Thus, not only agents such as thrombin and plasmin that cause the release of the contents of the platelet granules decrease platelet density, but ADP also has this effect. Platelets would be exposed to all of these stimuli during thromboembolic processes, and their effect on platelets may account for the decrease in platelet density observed previously in experiments with rabbits with indwelling aortic catheters. Agents that increase the concentration of cyclic AMP (cAMP) in platelets (PGE1, adenosine, dibutyryl cAMP, forskolin, and papaverine) also decreased platelet density. This effect persisted when the platelets were washed and resuspended in fresh medium and was also demonstrable in plasma. Platelet size was gradually increased by prostaglandin E1 (PGE1) which maintains platelets in a disc shape and does not cause the release of granule contents, indicating that the decrease in platelet density caused by PGE1 may be attributable to platelet swelling.