Influence of sevoflurane on the metabolism and renal effects of compound A in rats

BACKGROUND: The sevoflurane degradation product compound A is nephrotoxic in rats. In contrast, patient exposure to compound A during sevoflurane anesthesia has no clinically significant renal effects. The mechanism for this difference is incompletely understood. One possibility is that the metabolism and toxicity of compound A in humans is prevented by sevoflurane. However, the effect of sevoflurane on compound A metabolism and nephrotoxicity is unknown. Thus, the purpose of this investigation was to determine the effect of sevoflurane on the metabolism and renal toxicity of compound A in rats. METHODS: Male rats received 0.25 mmol/kg intraperitoneal compound A, alone and during sevoflurane anesthesia (3%, 1.3 minimum alveolar concentration, for 3 h). Compound A metabolites in urine were quantified, and renal function was evaluated by serum creatinine and urea nitrogen, urine volume, osmolality, protein excretion, and renal tubular histology. RESULTS: Sevoflurane coadministration with compound A inhibited compound A defluorination while increasing relative metabolism through pathways of sulfoxidation and beta-lyase-catalyzed metabolism, which mediate toxicity. Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity. CONCLUSIONS: Sevoflurane does not suppress compound A nephrotoxicity in rats in vivo. These results do not suggest that lack of nephrotoxicity in surgical patients exposed to compound A during sevoflurane anesthesia results from an inhibitory effect of sevoflurane on compound A metabolism and toxicity. Rather, these results are consistent with differences between rats and humans in compound A exposure and inherent susceptibility to compound A nephrotoxicity.     

不同剂量布托啡诺对胃癌根治术后患者静脉自控镇痛效能的比较

目的观察不同剂量的布托啡诺对胃癌根治术后患者静脉自控镇痛效能的比较。方法选择行胃癌根治的患者232例,ASA为Ⅰ～Ⅱ级。将232例患者随机分为布托啡诺静脉自控镇痛组和对照组,每组均为29例。其中布托啡诺组分为6个小组,分别是布托啡诺浓度为0.004%、0.005%、0.006%、0.007%、0.008%和0.009%的A1、A2、A3、A4、A5和A6组。对照组分为2个小组,分别是吗啡浓度为0.025%的B1组以及传统方法治疗B2组。在胃癌根治术后1d观察患者情况,详细记录患者的舒适度评分、镇静度评分、视觉模拟评分以及患者的不良反应与PCIA的总按压频率次数和实际用药情况。结果①A3～A6组以及B1组的VAS评分明显低于B2和A1、A2组,而BCS的评分要高于B2和A1、A2组（P〈0.05）。②A3～A6组的PCIA总压次数明显低于A1、A2组,然而用药量远远高于A1、A2两组（P〈0.05）。③B1组患者腹胀、恶心、呕吐等不良症状发生频率远远高于A1～A6以及B2组患者（P〈0.05）。A6组患者的嗜睡程度最高。A1、A2组需要其他镇痛药物辅助,镇痛效果才能达到A3～A6组。结论布托啡诺的浓度为0.006%、0.007%时,以0.0022～0.0026mg/（kg.h）的速率给药,负荷剂量为0.005mg/（kg.h）的静脉PCIA会获得最佳的镇痛疗效,并且不良反应的发生率极低,可以应用于相关临床疾病的治疗中。     

Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5

BACKGROUND: There is considerable unexplained interindividual variability in the clearance of alfentanil. Alfentanil undergoes extensive metabolism by cytochrome P4503A4 (CYP3A4). CYP3A5 is structurally similar to CYP3A4 and metabolizes most CYP3A4 substrates but is polymorphically expressed. Livers with the CYP3A5*1 allele contain higher amounts of the native CYP3A5 protein than livers homozygous for the mutant CYP3A5*3 allele. This investigation tested the hypothesis that alfentanil is a substrate for CYP3A5 and that CYP3A5 pharmacogenetic variability influences human liver alfentanil metabolism. METHODS: Alfentanil metabolism to noralfentanil and N-phenylpropionamide was determined in microsomes from two groups of human livers, characterized for CYP3A4 and CYP3A5 protein content: low CYP3A5 (2.0-5.2% of total CYP3A, n = 10) and high CYP3A5 (46-76% of total CYP3A, n = 10). Mean CYP3A4 content was the same in both groups. The effects of the CYP3A inhibitors troleandomycin and ketoconazole, the latter being more potent toward CYP3A4, on alfentanil metabolism were also determined. RESULTS: In the low versus high CYP3A5 livers, respectively, noralfentanil formation was 77 +/- 31 versus 255 +/- 170 pmol . min . mg, N-phenylpropionamide formation was 8.0 +/- 3.1 versus 20.5 +/- 14.0 pmol . min . mg, and the metabolite ratio was 9.5 +/- 0.4 versus 12.7 +/- 1.4 (P < 0.05 for all). There was a poor correlation between alfentanil metabolism and CYP3A4 content but an excellent correlation when CYP3A5 (i.e., total CYP3A content) was considered (r = 0.81, P < 0.0001). Troleandomycin inhibited alfentanil metabolism similarly in the low and high CYP3A5 livers; ketoconazole inhibition was less in the high CYP3A5 livers. CONCLUSION: In microsomes from human livers expressing the CYP3A5*1 allele and containing higher amounts of CYP3A5 protein, compared with those with the CYP3A5*3 allele and little CYP3A5, there was greater alfentanil metabolism, metabolite ratios more closely resembled those for expressed CYP3A5, and inhibitors with differing CYP3A4 and CYP3A5 selectivities had effects resembling those for expressed CYP3A5. Therefore, alfentanil is metabolized by human liver microsomal CYP3A5 in addition to CYP3A4, and pharmacogenetic variability in CYP3A5 expression significantly influences human liver alfentanil metabolism in vitro. Further investigation is warranted to assess whether the CYP3A5 polymorphism is a factor in the interindividual variability of alfentanil metabolism and clearance in vivo.     

Tissue expression, distribution, and regulation of PDE5

Phosphodiesterase 5 (PDE5) has been identified in many species. The three isoforms, PDE5A1, PDE5A2, and PDE5A3, differ only in their N-terminal sequence. PDE5A1 and PDE5A2 are ubiquitous, but PDE5A3 is specific to smooth muscle. The initial three exons (A1-A3-A2) of PDE5A, located on chromosome 4q26, are alternative first exons encoding the isoform-specific sequences. The PDE5A promoter overlaps with the A1-specific exon, while the PDE5A2 promoter is located between the A3- and A2-specific exons. Both respond to cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP) stimulation. The PDE5A2 promoter contains an Sp1-binding sequence critical for basal and cGMP/cAMP-inducible promoter activities. PDE5A is induced by adjacent sequences (enhancers) containing Sp1-binding sites. The potential role of PDE5A promoters in the tachyphylaxis effect of PDE5 inhibitors is currently being investigated. Preliminary data suggest that hypoxia might down-regulate PDE5A promoters, implying an involvement of PDE5 in stuttering priapism.     

Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma

ARID1A is a recently identified tumor suppressor gene that is mutated in approximately 50% of ovarian clear cell and 30% of ovarian endometrioid carcinomas. The mutation is associated with loss of protein expression as assessed by immunohistochemistry. In this study, we evaluated ARID1A immunoreactivity in a wide variety of carcinomas to determine the prevalence of ARID1A inactivation in carcinomas. Mutational analysis of ARID1A was carried out in selected cases. Immunoreactivity was not detected (corresponding to inactivation or mutation of ARID1A) in 36 (3.6%) of 995 tumors. Uterine low-grade endometrioid carcinomas showed a relatively high-frequency loss of ARID1A expression, as 15 (26%) of 58 cases were negative. The other tumor that had a relatively high-frequency loss of ARID1A expression was gastric carcinoma (11%). Mutational analysis showed 10 (40%) of 25 uterine endometrioid carcinomas; none of 12 uterine serous carcinomas and none of 56 ovarian serous and mucinous carcinomas harbored somatic ARID1A mutations. All mutations in endometrioid carcinomas were nonsense or insertion/deletion mutations, and tumors with ARID1A mutations showed complete loss or clonal loss of ARID1A expression. In conclusion, this study is the first large-scale analysis of a wide variety of carcinomas showing that uterine low-grade endometrioid carcinoma is the predominant tumor type harboring ARID1A mutations and frequent loss of ARID1A expression. These findings suggest that the molecular pathogenesis of low-grade uterine endometrioid carcinoma is similar to that of ovarian low-grade endometrioid and clear cell carcinoma, tumors that have previously been shown to have a high-frequency loss of expression and mutation of ARID1A.     

Influence of Sevoflurane on the Metabolism and Renal Effects of Compound A in Rats

Background: The sevoflurane degradation product compound A is nephrotoxic in rats. In contrast, patient exposure to compound A during sevoflurane anesthesia has no clinically significant renal effects. The mechanism for this difference is incompletely understood. One possibility is that the metabolism and toxicity of compound A in humans is prevented by sevoflurane. However, the effect of sevoflurane on compound A metabolism and nephrotoxicity is unknown. Thus, the purpose of this investigation was to determine the effect of sevoflurane on the metabolism and renal toxicity of compound A in rats.

Methods: Male rats received 0.25 mmol/kg intraperitoneal compound A, alone and during sevoflurane anesthesia (3%, 1.3 minimum alveolar concentration, for 3 h). Compound A metabolites in urine were quantified, and renal function was evaluated by serum creatinine and urea nitrogen, urine volume, osmolality, protein excretion, and renal tubular histology.

Results: Sevoflurane coadministration with compound A inhibited compound A defluorination while increasing relative metabolism through pathways of sulfoxidation and [beta]-lyase-catalyzed metabolism, which mediate toxicity. Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity.     

Identification of COL4A5 defects in Alport's syndrome by immunohistochemistry of skin

BACKGROUND: The COL4A3-COL4A4-COL4A5 network in the glomerular basement membrane is affected in the inherited renal disorder Alport's syndrome (AS). Approximately 85% of the AS patients are expected to carry a mutation in the X-chromosomal COL4A5 gene and 15% in the autosomal COL4A3 and COL4A4 genes. The COL4A5 chain is also present in the epidermal basement membrane (EBM). It is predicted that approximately 70% of the COL4A5 mutations prevent incorporation of this chain in basement membranes. METHODS: We investigated whether or not COL4A5 defects could be detected by immunohistochemical analysis of the EBM. Punch skin biopsies were obtained from 22 patients out of 17 families and two biopsy specimens from healthy males were used as controls. RESULTS: In four cases with the COL4A5 frameshift or missense mutations, the COL4A5 chain was either lacking from the EBM (male) or showed a focally negative pattern (female). In three other patients with a COL4A5 missense mutation, a COL4A3 and a COL4A4 mutation, respectively, the COL4A5 staining was normal. A (focally) negative EBM-COL4A5 staining was found in three patients of six families with a diagnosis of AS and in one family of a group of four families with possible AS. CONCLUSIONS: The (focal) absence of COL4A5 in the EBM of skin biopsy specimens can be used for fast identification of COL4A5 defects. Combined with polymorphic COL4A5 markers, both postnatal and prenatal DNA diagnosis are possible in the family of the patient.     

腺苷A2A受体激活缺血后处理保护皮瓣作用研究

目的：缺血后处理需要反复夹闭血管蒂,可能对血管造成机械性损伤。药物缺血后处理成为缺血后处理的发展方向。腺苷A2A是调控皮瓣炎症的关键靶点,进行相关研究进一步探究腺苷A2A激活缺血后处理对皮瓣有否保护作用。方法：健康成年新西兰大白兔,分为3组。A组为假手术组;B组为缺血再灌注损伤组;C组,再灌注前5min注射腺苷A2A激活剂。分别进行皮瓣存活率检测和ELISA检测TNF以及IL-6。结果：腺苷A2A激活剂组皮瓣存活率高,炎症因子检测活性低于缺血再灌注损伤组。结论：腺苷A2A激活剂缺血后处理可以抑制炎症因子,具有保护皮瓣作用。运用腺苷A2A受体激活缺血后处理可能成为保护皮瓣的新措施。     

Immunohistochemical expression of cyclin A in testicular biopsies of fertile and infertile men: correlation with the morphometry of seminiferous tubules

Cyclin A is a member of the cyclin family of proteins, which are required for both the mitotic and meiotic divisions that characterise spermatogenesis in human and other mammalian species. The data on cyclin A expression in various human spermatogenic disorders and its relationship to the morphology of seminiferous tubules are not well clarified. This study aimed to evaluate the immunohistochemical expression of cyclin A in testicular biopsies of different spermatogenic disorders correlating with the morphology of seminiferous tubules using morphometry tools. Immunohistochemical evaluation of cyclin A was carried out on testicular biopsies obtained from 48 infertile males (nonobstructive azoospermia) and 15 normal subjects together with using semiautomatic morphometric analysis for evaluation of seminiferous tubules. Cyclin A is expressed in 100% of normal and hypospermatogenesis groups and in 80% of maturation arrest group, with complete absence in Sertoli cell only group. In positive cases, cyclin A stained the nuclei of spermatogonia and primary spermatocytes with a higher intensity of expression in normal cases compared with infertile group. Cyclin A expression was significantly associated with the different examined morphometric parameters. Cyclin A is involved in both mitosis and meiosis of human spermatogenesis as it is expressed in spermatogonia and primary spermatocytes. Morphometry of human testis is intimately correlated with the testicular histopathology.     

The role of vitamin A in cancer

The differentiation and maintenance of epithelial tissues is a well-known function of vitamin A. The most dramatic expression of this is the antineoplastic effect. This biological activity of vitamin A is reviewed with regard to anticarcinogenesis, the reversal of transformation and a possible role in cancer therapy. A brief account is given of vitamin A absorption and transport in the body and the importance of varying levels of cellular binding proteins in normal and malignant tissues.     

The association of degeneration of the intervertebral disc with 5a/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene

It has been suggested that matrix metalloproteinase-3 (MMP-3, stromelysin-1) has an important role in the degeneration of intervertebral discs (IVDs). A human MMP-3 promoter 5A/6A polymorphism was reported to be involved in the regulation of MMP-3 gene expression. We suggest that IVD degeneration is associated with 5A/6A polymorphism. We studied 54 young and 49 elderly Japanese subjects. Degeneration of the lumbar discs was graded using MRI in the younger group and by radiography in the elderly. 5A/6A polymorphism was determined by polymerase-chain reaction-based assays. We found that the 5A5A and 5A6A genotype in the elderly was associated with a significantly larger number of degenerative IVDs than the 6A6A (p < 0.05), but there was no significant difference in the young. In the elderly, the IVD degenerative scores were also distributed more highly in the 5A5A and 5A6A genotypes (p = 0.0029). Our findings indicate that the 5A allele is a possible risk factor for the acceleration of degenerative changes in the lumbar disc in the elderly.     

Tuberculous destruction of the talus--a rare form of extrapulmonary skeletal TBC--a case report]

A 29 year old vietnamesian patient comes to an examination because of pain in the ankle one week after the arrival in Germany. The clinical examination is inconspicuous, x-ray pictures show a necrosis of the talus. A puncture is sterile. A partial astragalektomie is done. Histology demonstrates a tuberculosis.     

不同种类自酸蚀处理剂对牙釉质及牙本质微观结构的影响

目的：通过扫描电镜观察，比较研究自行研制的自酸蚀处理剂A1、A2、B1、B2与现有商品自酸蚀处理剂Contax、SE Bond处理牙釉质、牙本质的超微结构差异。方法：12颗人磨牙制得牙釉质、牙本质试件各24片，分别随机分为6组(n=4)。不同种类自酸蚀处理剂A1、A2、B1、B2、Contax、SE Bond分别进行处理后，扫描电镜观察。结果：B组对牙釉质、牙本质均有较强脱矿能力，与Contax组较为接近。A组对牙齿表面的脱矿能力相对较弱，与SE Bond组较为接近。结论：自行研制的自酸蚀处理剂A1、A2、B1、B2对牙釉质、牙本质有不同程度的酸蚀刻作用，基本达到了牙齿表面处理的目的。     

Influence of parent vessel dominancy on fluid dynamics of anterior communicating artery aneurysms

Background

Parent vessel plays an important role in aneurysm formation and rupture. The diameter of either the A1 arteries is the peculiar key controlling the flow of the anterior communicating artery (ACOMA) aneurysms (ANs).

Objective

The purpose is to study the effect of parent vessel dominancy, that is, the diameter of the A1 artery, on the flow characteristics of the ACOMA ANs.

Methods

Numerical simulations for the flow patterns in six artificial models have been studied. Three models are designed with aneurysms and three models without. The two A1s were equal in two models. In the other two models, the nondominant A1 diameters were decreased by 50%. Again, the nondominant A1s were decreased by another 50% in the last two models. Each pair was designed with and without aneurysms in the ACOMA.

Findings

The ACOMA shows lower velocity magnitudes and wall shear stresses when the two A1s are equal. However, if one A1 is dominant with a 50% difference from the other A1, there is higher shear stress on the ACOMA itself and in the inflow zone of the aneurysm that increases more with further reduction of the nondominant A1 by another 50%. An area of high corner pressure at the bifurcation of the dominant A1 into the ACOMA and A2 exists and increases in value with the decrease of diameter of the other nondominant A1.

Conclusion

Aneurysms located in the ACOMA with differences of 50% or more between the two A1s are subjected to more flow stresses.     

Pharmacogenetic Determinants of Human Liver Microsomal Alfentanil Metabolism and the Role of Cytochrome P450 3A5

Background: There is considerable unexplained interindividual variability in the clearance of alfentanil. Alfentanil undergoes extensive metabolism by cytochrome P4503A4 (CYP3A4). CYP3A5 is structurally similar to CYP3A4 and metabolizes most CYP3A4 substrates but is polymorphically expressed. Livers with the CYP3A5*1 allele contain higher amounts of the native CYP3A5 protein than livers homozygous for the mutant CYP3A5*3 allele. This investigation tested the hypothesis that alfentanil is a substrate for CYP3A5 and that CYP3A5 pharmacogenetic variability influences human liver alfentanil metabolism.

Methods: Alfentanil metabolism to noralfentanil and N-phenylpropionamide was determined in microsomes from two groups of human livers, characterized for CYP3A4 and CYP3A5 protein content: low CYP3A5 (2.0-5.2% of total CYP3A, n = 10) and high CYP3A5 (46-76% of total CYP3A, n = 10). Mean CYP3A4 content was the same in both groups. The effects of the CYP3A inhibitors troleandomycin and ketoconazole, the latter being more potent toward CYP3A4, on alfentanil metabolism were also determined.

Results: In the low versus high CYP3A5 livers, respectively, noralfentanil formation was 77 +/- 31 versus 255 +/- 170 pmol [middle dot] min-1 [middle dot] mg-1, N-phenylpropionamide formation was 8.0 +/- 3.1 versus 20.5 +/- 14.0 pmol [middle dot] min-1 [middle dot] mg-1, and the metabolite ratio was 9.5 +/- 0.4 versus 12.7 +/- 1.4 (P < 0.05 for all). There was a poor correlation between alfentanil metabolism and CYP3A4 content but an excellent correlation when CYP3A5 (i.e., total CYP3A content) was considered (r2 = 0.81, P < 0.0001). Troleandomycin inhibited alfentanil metabolism similarly in the low and high CYP3A5 livers; ketoconazole inhibition was less in the high CYP3A5 livers.     

Primary sarcoma of penis

A case of primary sarcoma of the penis is reported. A very slow growth rate of this tumor was observed and prompted conservative treatment. A review of the literature is included. More cases of penile sarcoma should be reported in order to study the not well-documented natural history of this disease.     

A possible regulatory role of glyoxalase I in cell viability of human prostate cancer

The medial parieto-occipital cortex is a central node in the dorsomedial visual stream. Recent physiological studies in the macaque monkey have demonstrated that the medial parieto-occipital cortex contains two areas, the visual area V6 and the visuomotor area V6A. Area V6 is a retinotopically organized visual area that receives form and motion information directly from V1 and is heavily connected with the other areas of the dorsal visual stream, including V6A. Area V6A is a bimodal visual/somatosensory area that elaborates visual information such as form, motion and space suitable for the control of both reaching and grasping movements. Somatosensory and skeletomotor activities in V6A affect the upper limbs and involve both the transport phase of reaching and grasping movements. Finally, V6A is strongly and reciprocally connected with the dorsal premotor cortex controlling arm movements. The picture emerging from these data is that the medial parieto-occipital cortex is well equipped to control both proximal and distal movements in the online visuomotor guidance of prehension. In agreement with this view, selective V6A lesions in monkey produce misreaching and misgrasping with the arm contralateral to the lesion in visually guided movements. These deficits are similar to those observed in optic ataxia patients and suggest that human and monkey superior parietal lobules are homologous structures, and that optic ataxia syndrome is the result of the lesion of a 'human' area V6A.     

Value of glycosylated haemoglobin determination in diabetic pregnancy

A single measurement of total maternal glycosylated haemoglobin (Hb A1) in the late third trimester of a diabetic pregnancy is of limited value in assessing diabetic control. There was no significant correlation between maternal Hb A1 values and neonatal C-peptide values or birth-weight ratios. An isolated Hb A1 measurement is not sufficiently sensitive to monitor the control of diabetes during pregnancy nor is it useful in predicting perinatal outcome.     

Anatomopathology of non-tumoral aqueductal stenosis

The aqueduct (A) is the most common site of intraventricular blockade of CSF flow. There are multiple causes of its obstruction which can be classified as congenital or acquired, but their morphological differentiation is often impossible, since in both human and experimentally induced obstructions of the A. various histological changes (narrowing, forking, gliosis) may occur. Occlusion of the A. results in internal hydrocephalus that may arise before or after birth, but in some forms of communicating hydrocephalus stenosis of the A. occurs as a secondary phenomenon due to compression of midbrain or other functional CSF block. The major types of non-tumoral stenosis of the A. include: Hereditary varieties occurring as X-linked recessive trait often as part of a malformation syndrome (Edwards et al., 1961) and rarely without sex-linkage. A. stenosis may be a cause or a consequence of hereditary hydrocephalus. Congenital obstruction of A. co-existing with other CNS malformations, e.g. with spina bifida and the Arnold-Chiari malformation often associated with hydrocephalus, or with hydranencephaly where A. stenosis is primary or secondary in origin. Gliotic obstruction as a common part of widespread ependymitis or sequelae of pre-, neonatal and infantile meningitis, toxoplasmosis or viral infections, less often due to organized intraventricular hemorrhage. Rare septum formation at the caudal end of the A. as minimal form of stenosis. Rare compression of A. by vascular malformations, retrocerebellar cysts (Dandy-Walker syndrome), etc. Experimentally induced obstructions of the A. due to nutritional (vitamin deficiencies), infectious (intrauterina, postnatal infections with rheo-, paramyxo-, arboviruses, etc.) causing non-inflammatory obstructions, and hereditary factors (congenital A. stenosis in mouse mutants) often show parallels to human disease. Their value in etiologic research on non-tumoral aqueductal stenosis is discussed.