人白介素- 4对牛血管内皮细胞保护作用的研究

目的:研究人白介素-4(hIL-4)对经TNF-α活化的牛主动脉内皮细胞(BAEC)的保护作用。方法:用不同浓度的hIL-4与BAEC共孵育2h后,再与4μg/L的TNF-α共孵育6h或18h。应用细胞ELISA方法,检测BAEC表面的E选择素和ICAM-1的表达;用MTT比色法测定hIL-4对BAEC活性的影响。结果:在一定浓度内用hIL-4预处理BAEC后,能明显抑制TNF-α诱导活化BAEC上的E选择素与ICAM-1的表达,并呈现一定的剂量依赖性。用MTT比色法测定BAEC活性的实验表明,各实验组BAEC的活性与对照组无明显差异性。结论:hIL-4能明显抑制TNF-α诱导活化的BAEC表达E选择素与ICAM-1;hIL-4对BAEC的正常功能具有一定的保护作用。     

Evidence for central reorganization of ventilatory chemoreflex pathways in the cat during regeneration of visceral afferents in the carotid sinus nerve

There are two sets of peripheral arterial chemoreceptors in the cat, the carotid bodies innervated by the carotid sinus nerve and the aortic bodies with afferents in the aortic depressor nerves. Reflex stimulation of ventilation in response to hypoxia is abolished acutely after interrupting the sensory pathway from the carotid body chemoreceptors in the cat even though the reflex pathway from the aortic body chemoreceptors is intact. However, in chronically maintained preparations, there is a restoration of the hypoxic response which is mediated by the aortic chemoreflex pathway. It was proposed that restoration was due to a ‘central reorganization’ of chemoreflex pathways which followed interruption of the sensory pathway from the carotid bodies and that the reorganization enhanced the efficacy of the aortic ventilation chemoreflex. This proposal was tested in the present experiments by measuring reflex ventilatory and cardiovascular responses to electrical stimulation of the sensory nerves containing aortic and carotid chemoreceptor afferents following bilateral interruption of carotid sinus nerves and carotid body resection. Responses measured acutely (1–6 h) after interruption were compared with those measured 60–80 and 110–140 days later. At 60–80 days, a chemoreflex response (increase in tidal volume of ventilation) to stimulation of the interrupted carotid sinus sensory pathway was markedly attenuated while the response to stimulation of the uninterrupted pathway in aortic depressor nerves was enhanced. At 110–140 days, the tidal volume response to carotid sinus nerve stimulation was greatly enhanced while the aortic depressor nerve response declined from the elevated level. There were significant but less pronounced changes in the response of other ventilatory and cardiovascular variables to aortic depressor nerve and carotid sinus nerve stimulation.The results support the idea that there is a ‘central reorganization’ of chemoreflex pathways which is reflected functionally by changes in the efficacy of reflexes evoked from aortic depressor nerve and carotid sinus nerve. The changes are analagous to those occurring in somatic reflexes during regeneration of sensory nerves. It is suggested that the changes in efficacy of carotid sinus nerve reflexes are due to a degenerative loss of synapses of the central projections of interrupted carotid sinus nerve sensory axons (degenerative atrophy) and subsequent regenerative like changes (regenerative proliferation) in the central projections. The changes in the efficacy of aortic depressor nerve reflexes may be attributed to formation of new synapses by converging central projections of this uninterrupted pathway (reactive synaptogenesis) and subsequent regression of the newly formed synapses.     

升主动脉瘤明胶酶活性变化的实验研究

目的 探讨明胶酶在升主动脉瘤形成过程中的活性变化及意义. 方法 将35只Wistar大鼠随机分为对照组和实验组.采用升主动脉缩窄鼠制备升主动脉瘤模型.于术后3～5个月取升主动脉,应用明胶酶谱分析及薄膜原位酶谱法检测动脉瘤明胶酶的活性改变. 结果 正常动脉壁外膜无或极少有明胶酶活性;动脉瘤壁的中膜与外膜明胶酶活性明显增强. 结论 明胶酶活性升高可能在升主动脉瘤形成过程中起重要作用.     

Pitfalls in acid/base experiments with conscious dogs

Arterial pH and blood gases were measured at intervals in conscious dogs after their first human contact of the day. Blood was sampled through an indwelling catheter in the aorta without disturbing the animals. It appeared that in the first 90 min arterial PO₂, oxygen saturation and haemoglobin concentration significantly declined. PCO₂ and pH changed less consistently when the acid/base status of the dogs was normal, but when a non-respiratory acidosis was present there was a significant decrease in pH and a significant increase in PCO₂. Arterial pH and blood gases were also measured before and after feeding the animals. It appeared that an appreciable metabolic alkalosis developed within 2 h after a meal. The alkaline tide was accompanied by a trend to higher values for PCO₂. It is concluded that, after a period of seclusion, renewed human contact causes behavioural changes in a dog, which may result in appreciable transitory changes in arterial pH and blood gas values. Blood sampling from conscious dogs should therefore take place after a proper period of habituation; preferably, a few samples should be taken at intervals to check that a steady state has been reached. If possible, blood should be collected before feeding; in any case the relationship in time of blood sampling to feeding should be constant throughout.     

The cholesteryl ester transfer protein (CETP) locus as a candidate gene in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a relatively common disease of the elderly presenting as progressive dilatation of the abdominal aorta. The condition shows a pronounced tendency to cluster in families, indicating a genetic component in the disease aetiology. We have screened the cholesteryl ester transfer protein (CETP) gene, which has been proposed as a candidate gene in AAA, by means of SSCP, DNA sequencing and restriction analysis in a cohort of patients with AAA and a matching control group drawn from the Irish population. The analysis has demonstrated sequence variation at four sites in the CETP gene: an A-T transversion in exon 9 (producing a Lys309-Stop codon substitution), a G-A transition in exon 14 (producing a conservative Va1421-Ile substitution), a C-T transition in intron 12 and a G-A transition in intron 15. None of the last three sites corresponded with sites of functional significance in the protein, suggesting that this reflects neutral polymorphism at the CETP locus. Furthermore, the frequencies of these four polymorphisms in the AAA patient and control groups were not significantly different. These data therefore suggest that CETP may be excluded as a candidate gene in abdominal aortic aneurysm.     

The genetic basis of Turner syndrome aortopathy

Our goal is to identify the genetic underpinnings of bicuspid aortic valve and aortopathy in Turner syndrome. We performed whole exome sequencing on 188 Turner syndrome study subjects from the GenTAC registry. A gene‐based burden test, SKAT‐O, was used to evaluate the data using bicuspid aortic valve (BAV) and aortic dimension z‐scores as covariates. This revealed that TIMP3 was associated with BAV and increased aortic dimensions at exome‐wide significance. It had been previously shown that genes on chromosome Xp contribute to aortopathy when hemizygous. Our analysis of Xp genes revealed that hemizygosity for TIMP1, a functionally redundant paralogue of TIMP3, increased the odds of having BAV aortopathy compared to individuals with more than one TIMP1 copy. The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles synergistically increased the risk for BAV aortopathy to nearly 13‐fold. TIMP1 and TIMP3 are tissue inhibitors of matrix metalloproteinases (TIMPs) which are involved in development of the aortic valve and protection from thoracic aneurysms. We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.     

Constitutive activation of the PI3K‐AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome

Kosaki overgrowth syndrome is a recently described syndrome characterized by distinctive facial features, brain white matter lesions, and developmental delay. Germline activating heterozygous PDGFRB mutations have been reported in this condition. Systemic connective tissue‐type findings have been described in some individuals. We describe a 19‐year‐old Caucasian female with a history of hydrocephalus, Dandy–Walker malformation, cervical spine arachnoid cyst, progressive scoliosis, and overgrowth. Her physical exam included distinctive craniofacial dysmorphism, as well as soft and hyperextensible skin. Cardiovascular imaging during adolescence revealed saccular aneurysms in both coronary artery systems and subtle tortuosity of the cervical vertebral arteries. Exome sequencing trio analysis identified a de novo previously reported pathogenic variant in PDGFRB, c.1696T>C (p.[Trp566Arg]). Further functional studies included platelet‐derived growth factor cellular metabolic pathway activity that confirmed the variant causes a constitutive activation of the PI3K‐AKT pathway. This is the first report to characterize the activating nature of this PDGFRB variant. We also highlight the connective tissue findings seen in Kosaki overgrowth syndrome and recommend baseline echocardiographic evaluation in all individuals with this condition with particular emphasis on coronary arteries.     

Intramural sarcoma of the carotid artery with adventitial inflammation and fibrosis resembling 'inflammatory aneurysm'

A rare case Is descrlbed of an Intramural sarcoma of the rlght common carotld artery coexistlng wlth adventitial inflammation and flbrosls, resembllng 'inflammatory aneurysm', which was resected from a 33-yearold Japanese woman who had presented with a pulsatile mass on the rlght side of the anterior neck. Grossly, the wall of the carotld artery showed an intimal tear with dlssectlon of the medla filled with thrombus. A graylsh area, abutting directly onto the dlssected space and Involving the media and inner adventltia, was composed of a-smooth muscle actin-positive and desmln-negative polygonal and splndle cells with large bluntended nuclei and coarse granular chromatin arranged Into a well-organized Interlacing bundle pattern. This portlon was thus considered to represent lelomyosarcoma. White to yellow-tan fibrotic tissue present in the adventitial area consisted of extensive lamellar fibrosis wlth scattered focl of lymphoplasmacytlc aggregates and obliterated arteries, and lacked atypical spindle and polygonal cells. These changes accorded with the histopathologlcal findlngs hitherto described in cases of 'inflammatory aneurysm', which is known to almost exclusively involve the abdominal aorta. We conslder this case unique In that the leiomyosarcoma involved an artery other than the aorta, wlth an 'inflammatory aneurysm'-like reaction in the same she. The posslble relatlonship between these two condltions Is dlscussed.     

Morphological and functional characteristics of myocytes isolated from human left ventricular aneurysms

Isolated single myocytes were prepared from myocardium of developing ventricular aneurysms and from myocardium within the scar of chronic ventricular aneurysms. The morphology and function of the individual cells were compared. The cells from developing aneurysms were rod-shaped, with a distinct sarcomeric structure, but did not contract even in the presence of high calcium concentrations. The sarcomere length was significantly higher than that of cells from chronic aneurysms and approached the theoretical point at which no contraction can occur. Cells from chronic aneurysms were either rod-shaped and contractile, or rounded due to hypercontracture of the myofilaments. Electron microscopy of cells from developing aneurysms confirmed the presence of elongated sarcomeres, a loss of the actin-myosin interdigitation, and damage to the contractile proteins which was particularly evident in the thin filaments. Cells with similar characteristics have also been isolated from a ruptured, ischaemic papillary muscle. These changes, which are due either to ischaemia or to overstretching of cells, may account for the weakness of the wall of developing aneurysms and be a cause of rupture or enlargement.