11β-Hydroxysteroid dehydrogenase type 1-driven cortisone reactivation regulates plasminogen activator inhibitor type 1 in adipose tissue of obese women

BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of the fibrinolytic system and contributes to an increased risk of atherothrombosis in insulin-resistant obese patients. In adipose tissue, we have shown that PAI-1 is synthesized mainly in the visceral stromal compartment and is positively regulated by glucocorticoids. We have demonstrated that adipose tissue expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), an enzyme that catalyzes the conversion of inactive cortisone to active cortisol, is exaggerated in obese patients. OBJECTIVES: We hypothesized that increased action of 11beta-HSD-1 in adipose tissue of obese subjects may contribute to PAI-1 overproduction. PATIENTS AND METHODS: Using in situ hybridization, we studied the expression of the mRNAs coding for PAI-1 and 11beta-HSD-1 in the stromal compartment of visceral adipose tissue obtained from obese women. The regulation of PAI-1 secretion from in vitro incubated tissue explants was also investigated. RESULTS: Regression analysis showed a significant positive linear relationship between PAI-1 and 11beta-HSD-1 mRNAs expression. In vitro incubation of adipose tissue explants demonstrated that cortisone stimulated PAI-1 gene expression and secretion, and that these effects were inhibited by co-incubation with the 11beta-HSD inhibitor, glycyrrhetinic acid. CONCLUSIONS: Our data demonstrate that 11beta-HSD-1-driven cortisone reactivation regulates adipose PAI-1 synthesis and secretion. They suggest that the increased PAI-1 synthesis and secretion observed in obese patients can be also related, at least in part, to an increased local conversion of cortisone to cortisol. Therefore, local cortisol metabolism in adipose tissue may be involved in increasing the risk of cardiovascular disease in obese subjects.     

The synthetic RGDS peptide inhibits the binding of fibrinogen lacking intact alpha chain carboxyterminal sequences to human blood platelets

The alpha chain 572-574 Arg-Gly-Asp sequence of fibrinogen appears to play only a minor role in platelet aggregation based on the ability of fibrinogen preparations lacking alpha chain carboxyterminal segments to support platelet aggregation, but synthetic Arg-Gly-Asp-Ser (RGDS) peptides are capable of inhibiting platelet aggregation and fibrinogen binding. The present study thus examined the ability of RGDS peptides to inhibit platelet interactions with a plasmic degradation product of fibrinogen (8D-50) that resembles an intermediate fragment X. Gel- filtered, human blood platelets suspended in 0.01 mol/L HEPES-buffered modified Tyrode's solution, pH 7.5, were stimulated with 20 mumol/L adenosine diphosphate and the binding of 125I-labeled 8D-50 or intact fibrinogen (0.01 to 0.6 mg/mL) assessed in the presence of 0 to 117 mumol/L RGDS. The data revealed that RGDS decreased the apparent affinity of 8D-50 and intact fibrinogen for platelets but did not affect the maximum number of binding sites. RGDS thus appears to be a competitive inhibitor not only of intact fibrinogen (Ki = 12 +/- 2 mumol/L) but also of 8D-50 (Ki = 15 +/- 3 mumol/L) (mean +/- SD, n = 3).     

The C-terminal sequences of the gamma 57.5 chain of human fibrinogen constitute a plasmin sensitive epitope that is exposed in crosslinked fibrin

The gamma chain of human plasma fibrinogen is heterogeneous with three forms differing in length at the C-terminus. Alternative RNA splicing produces two gamma chain mRNAs encoding gamma 50 and gamma 57.5 polypeptides, while fibrinogen gamma 55 is produced by post- translational modification of the gamma 57.5 chain. The composition of purified variant gamma chain fibrinogens, which comprise 10% to 13% total plasma fibrinogen, is predominantly heterodimeric (A alpha, B beta, gamma 50/gamma 55 or A alpha, B beta, gamma 50/gamma 57.5), whereas the composition of purified fibrinogen with the major form of the gamma chain is homodimeric (A alpha, B beta, gamma 50/gamma 50). These gamma chain variations interrupt sequences that mediate platelet- fibrinogen interactions. Therefore, the structure and function of gamma 57.5 C-terminal sequences were investigated using synthetic peptides and a specific monoclonal antibody (MoAb), L2B. The L2B epitope was localized and included gamma 57.5 chain residues 409-412 (Arg-Pro-Glu- His), as determined by differential enzyme-linked immunosorbent assay (ELISA) reactivity with a His-412 deleted synthetic peptide and by Western blot analysis of plasmin cleaved fibrinogen gamma 57.5. L2B had no effect on adenosine diphosphate (ADP)-induced platelet aggregation supported by either fibrinogen gamma 50 or gamma 57.5. High concentrations (0.5 to 1 mmol/L) of synthetic peptide gamma 57.5 405- 416 only weakly inhibited ADP-induced platelet aggregation supported by either fibrinogen gamma 50 or gamma 57.5. Binding of fibrinogen gamma 50 (IC50 = 780 mumol/L) or gamma 57.5 (IC50 = 650 mumol/L) to ADP- stimulated platelets was weakly inhibited, and MoAb L2B failed to inhibit fibrinogen gamma 57.5 binding. Peptide gamma 57.5 408-416 failed to dissociate platelet-bound fibrinogens. These data indicate that the gamma 408-416 sequence of fibrinogen gamma 55 or gamma 57.5 alone is unlikely to bind to the platelet fibrinogen receptor, glycoprotein llb-llla (GPllb-llla), in support of platelet aggregation under physiologic conditions. The sequence recognized by L2B does not resemble known GPllb-llla binding site peptide sequences [Arg-Gly-Asp- Ser (RGDS) or gamma 50 400-411] as determined by competitive inhibition ELISA comparing these binding site synthetic peptides with gamma 57.5 408-416. This epitope is available for binding MoAb L2B in gamma 55 or gamma 57.5 chain dimers and binds to all gamma 57.5 408-416 epitopes equally in non-crosslinked and factor Xllla crosslinked fibrin clots.(ABSTRACT TRUNCATED AT 400 WORDS)     

Chronic expression of P-selectin on endothelial cells stimulated by the T-cell cytokine, interleukin-3

P-selectin expressed on the surface of endothelium mediates leukocyte adhesion in vitro and rolling in vivo. Several inducers of cell-surface P-selectin expression on endothelial cells (EC) have previously been identified, all of which yield transient cell-surface expression of P- selectin lasting minutes to a few hours. We now show that a T- lymphocyte product, interleukin-3 (IL-3), stimulates the long-term endothelial cells (HUVEC). IL-3 induced cell-surface P-selectin expression in two phases. An initial peak at 10 minutes was followed by a prolonged upregulation beginning 16 hours after IL-3 addition and lasting at least 4 days. The level of P-selectin expression induced by IL-3 added for 48 hours was similar to that induced by treatment of HUVEC for 10 minutes with thrombin, and the effect of adding IL-3 for 48 hours followed by thrombin for 10 minutes was additive. Induction of cell-surface P-selectin expression by IL-3 was blocked by pretreatment of EC with a blocking monoclonal antibody against the IL-3 receptor alpha-chain. Lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF alpha) and a mutant form of IL-3 with decreased potency did not induce cell-surface P-selectin expression after 48 hours' incubation with HUVEC, suggesting that the effect was specific to IL-3. The increase in cell-surface P-selectin expression occurring after 16 hours of incubation with IL-3 was accompanied by a similar prolonged increase in the steady-state mRNA level that was not observed at 10 minutes after IL-3 addition. As T-lymphocyte infiltration is a hallmark of chronic inflammation, our observations suggest that the secretion of IL-3 by T lymphocytes may serve to maintain the inflammatory state during chronic inflammation.     

Sonographic Biometry of Normal Kidney Dimensions among School-age Children in Nsukka,Southeast Nigeria

Background:

Some kidney diseases are usually associated with changes in kidney size.

Objective:

To determine sonographically the normal limits and percentile curves of the kidney dimensions according to age, gender and somatometric parameters among school-age children.

Methods:

A prospective cross-sectional research design and convenience sampling method were utilized. Participants included 947 normal subjects (496 boys and 451 girls) aged 6–17 years old. The sonographic examination was performed on a Shenzhen DP-1100 machine with 3.5 MHz convex transducer. Longitudinal and transverse dimensions of the kidneys were obtained in coronal plane with the subject in the supine or left lateral decubitus position.

Results:

The means of right and left kidney lengths in mm were 79.6 ± 8.1 and 81.6 ± 8.3, respectively while those of the right and left kidney widths in mm were 35.03 ± 3.6 and 35.09 ± 3.6, respectively. Dimensions of the kidneys were not statistically different in boys and girls (p > 0.05). There was a statistically significant difference between right and left kidney length (p < 0.05). Height correlated best with both kidney lengths. Thus the normal limits, prediction models and percentile curves of kidney lengths were established with respect to height.

Conclusion:

Sonographic determination of pathologic changes in the size of the kidney necessitates knowing the normal ranges of its length especially with respect to height in school-age children.     

健康信念模式在早期宫颈癌患者健康教育中应用观察

目的探讨健康信念模式在早期宫颈癌患者健康教育中应用价值。方法选取该院2013年1月—2014年6月收治的90例早期宫颈癌患者,随机分为两组,对照组和观察组各45例,对照组患者应用标准健康计划指导,观察组患者实施健康信念模式,比较两组患者采用不同的健康教育方式后患者对宫颈癌基本知识、自我保健知识的掌握情况。结果观察组患者对疾病知晓和掌握程度明显优于对照组,观察组掌握率高达93.3%（42/45）,与对照组的75.6%（34/45）差异有统计学意义（P〈0.05）;观察组自我保健知识掌握率为95.6%（43/45）,对照组掌握率为82.2%（37/45）,差异有统计学意义（P〈0.05）;观察组对护理工作满意度显著高于对照组（P〈0.05）。结论对早期宫颈癌患者健康教育中采用健康信念模式具有明显的临床价值,有助于提升患者对疾病的认识,增强健康信念,养成良好的生活习惯,积极主动的做好预防措施,有效降低并发症发生率,值得在临床上进一步推广。     

Gestational trophoblastic neoplasia: diagnosis with Doppler US

The sonographic appearance of gestational trophoblastic neoplasia is nonspecific and also seen in complete or partial hydatidiform mole, hydropic degeneration, degenerating fibroids, or ovarian dysgerminomas. Correlation with the serum human chorionic gonadotropin (hCG) level may be helpful since levels exceeding 100,000 IU/L are strongly suggestive of gestational trophoblastic neoplasia. However, low hCG levels may also be found in the presence of this disease. The authors studied six patients who were suspected of having gestational trophoblastic neoplasia. Three of the six proved to have incomplete abortions or molar degeneration. Doppler ultrasound (US) was used to record the signal in the uterine arteries of these patients. The signals were compared with those of three nongravid volunteers and three patients in the first trimester of pregnancy. Analysis of the signals in the uterine artery showed higher systolic and diastolic Doppler shifts in gestational trophoblastic neoplasia when compared with postabortal, gravid, and nongravid signals. These preliminary results indicate that Doppler US has the potential to be clinically useful in the diagnosis of gestational trophoblastic neoplasia.     

Linkage of polymorphic congenital cataract to the gamma-crystallin gene locus on human chromosome 2q33-35

Cataract is one of the major causes of blindness in humans. We describe here an autosomal dominant polymorphic congenital cataract (PCC) which is characterised by wide variations in phenotype of non-nuclear lens opacities, even among affected members of the same family. PCC families included a large, unique pedigree (254 members, 103 affected individuals), and genetic linkage was conducted using a variety of polymorphic markers. Evidence for linkage was found for chromosome 2q33- 35 with PCC mapping near D2S72 and TNP1. A tri-nucleotide microsatellite marker for gamma-crystallin B gene (CRYG1) was found to co-segregate with PCC and yielded a maximum lod score of 10.62 at (theta = 0). A multipoint analysis demonstrated that the most probable location of the PCC gene was within an 8 cM genetic interval containing the gamma-crystallin gene cluster. These data provide strong evidence of the existence of an autosomal dominant mutation for PCC in or near the gamma-crystallin gene cluster. This defect is characterised by complete penetrance but variable expression of the cataract phenotype. Our study also suggests that non-nuclear human cataracts might be caused by some abnormality in gamma-crystallin genes.      

THE PHYSICIAN IN COURT: A VIEW FROM THE BENCH

Only lawyers and judges-and not even all of them-look forward to being in court. For the physician it is usually not an experience sought or savoured. Yet some physicians are in court more frequently than some lawyers because they are expert witnesses or because they have treated a person who is before the court in a civil or criminal case. There is also the physician who is sued and is thus a defendant. I believe it important that physicians know the basic ingredients of a civil action. I will be drawing on my experience as a trial judge for eight years and an Alberta Court of Appeal judge for five, and as a former professor in the faculties of law and medicine at the University of Alberta, to present the perspective from the bench on civil non-jury actions.