Maintenance of growth in cystic fibrosis despite reduction in pancreatic enzyme supplementation

Twenty one children with cystic fibrosis were advised to decrease their pancreatic enzyme supplement (PES) dose to less than 10,000 units lipase/kg/day. Mean PES dosage was significantly decreased in 15 patients from 18,380 to 8647 units lipase/kg/day. There were no significant changes in energy or fat intake, but there were significant increases in weight SD score, height SD score, and weight/height ratio.     

组成型αB晶体蛋白在热休克蛋白核转录因子1敲除小鼠心肌中的表达

目的:了解热休克蛋白核转录因子1(HSF1)对小鼠心肌组成型αB晶体蛋白(αB-Crystallin,αBC)表达的影响.方法:用western blot和免疫组织化学的方法,测定组成型αBC在HSF1基因野生型(hsf1+/+)和HSF1基因敲除型(hsf1-/-)小鼠心肌中的表达.结果:αBC在hsf1-/-和hsf1+/+小鼠心肌表达量分别为68.42±4.16和100.00±7.58(心肌可溶性组分,P＜0.05),20.35±1.01和37.55±1.91(心肌不可溶性组分,P＜0.05);免疫组化显示αBC在hsf1-/-心肌细胞内的表达信号较hsf1+/+明显减弱.结论:HSF1基因是介导组成型αBC基因表达重要的、但不是惟一的因子.     

丹参通络解毒汤联合内皮祖细胞移植对心肌缺血再灌注损伤大鼠促血管新生作用的研究

目的探讨丹参通络解毒汤(DSTLJD)联合内皮祖细胞(endothelial progenitor cells, EPCs)移植对心肌缺血再灌注损伤(ischemic reperfusion injury, IRI)模型大鼠促血管新生作用的影响及其机制。方法采用密度梯度离心法及差数贴壁法分离和培养EPCs,采用免疫荧光法鉴定EPCs。通过结扎左冠状动脉左前降支的方法建立IRI模型,采用随机数字表法分为SH组(假手术组)、IRI组(模型组)、EPCs组(EPCs移植组)、DSTLJD组(丹参通络解毒汤组)、DSTLJD+EPCs组(丹参通络解毒汤+EPCs移植),每组10只。4周后,采用HE染色法观察心肌组织的病理形态,用免疫组化法测定各组大鼠心肌微血管计数(microvessel count, MVC)、心肌微血管密度(microvessel density, MVD),并检测各组大鼠血管内皮生长因子(vascular endothelial growth factor, VEGF)、碱性成纤维生长因子(basic fibroblast growth factor, bFGF)的蛋白表...     

Crystallins Play a Crucial Role in Glaucoma and Promote Neuronal Cell Survival in an In Vitro Model Through Modulating Müller Cell Secretion

PurposeThe aim of this study was to explore the roles of crystallins in the context of aging in glaucoma and potential mechanisms of neuroprotection in an experimental animal model of glaucoma.MethodsIntraocular pressure (IOP) was significantly elevated for 8 weeks in animals at different ages (10 days, 12 weeks, and 44 weeks) by episcleral vein cauterization. Retinal ganglion cells (RGCs) were quantified by anti-Brn3a immunohistochemical staining (IHC). Proteomics using ESI-LTQ Orbitrap XL-MS was used to analyze the presence and abundance of crystallin isoforms the retinal samples, respectively. Neuroprotective property and localization of three selected crystallins CRYAB, CRYBB2, and CRYGB as most significantly changed in retina and retinal layers were determined by IHC. Their expressions and endocytic uptakes into Müller cells were analyzed by IHC and Western blotting. Müller cell secretion of neurotrophic factors into the supernatant following CRYAB, CRYBB2, and CRYGB supplementation in vitro was measured via microarray.ResultsIOP elevation resulted in significant RGC loss in all age groups (P < 0.001). The loss increased with aging. Proteomics analysis revealed in parallel a significant decrease of crystallin abundance – especially CRYAB, CRYBB2, and CRYGB. Significant neuroprotective effects of CRYAB, CRYBB2, and CRYGB after addition to retinal cultures were demonstrated (P < 0.001). Endocytic uptake of CRYAB, CRYBB2, and CRYGB was seen in Müller cells with subsequent increased secretion of various neurotrophic factors into the supernatant, including nerve growth factor, clusterin, and matrix metallopeptidase 9.ConclusionsAn age-dependent decrease in CRYAB, CRYBB2, and CRYGB abundance is found going along with increased RGC loss. Addition of CRYAB, CRYBB2, and CRYGB to culture protected RGCs in vitro. CRYAB, CRYBB2, and CRYGB were uptaken into Müller cells. Secretion of neurotrophic factors was increased as a potential mode of action.     

Treatment of gonadotropin dependent precocious puberty due to hypothalamic hamartoma with gonadotropin releasing hormone agonist depot.

The gonadotropin releasing hormone (GnRH) secreting hypothalamic hamartoma (HH) is a congenital malformation consisting of a heterotopic mass of nervous tissue that contains GnRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle. HH is a well recognised cause of gonadotropin dependent precocious puberty (GDPP). Long term data are presented on eight children (five boys and three girls) with GDPP due to HH. Physical signs of puberty were observed before 2 years of age in all patients. At presentation with sexual precocity, the mean height standard deviation (SD) for chronological age was +1.60 (1.27) and the mean height SD for bone age was -0.92 (1.77). Neurological symptoms were absent at presentation and follow up. The hamartoma diameter ranged from 5 to 18 mm and did not change in six patients who had magnetic resonance imaging follow up. All patients were treated clinically with GnRH agonists (GnRH-a). The duration of treatment varied from 2.66 to 8.41 years. Seven of the eight children had satisfactory responses to treatment, shown by regression of pubertal signs, suppression of hormonal levels, and improvement of height SD for bone age and predicted height. One patient had a severe local reaction to GnRH-a with failure of hormonal suppression and progression of pubertal signs. It seems that HH is benign and that GnRH-a treatment provides satisfactory and safe control for most children with GDPP due to HH.     

Complete form of androgen insensitivity syndrome in Brazilian patients due to P766A mutation in the androgen receptor

Androgen insensitivity syndrome (AIS) is a rare X-linked disorder, caused by mutations in the androgen receptor gene (AR), associated with a variety of phenotypes in 46,XY individuals. We studied two 23 year-old twin-sisters with female social sex referred due to primary amenorrhea, who exhibited bilateral palpable gonads in the inguinal region and a 46,XY karyotype. The uterus was absent in pelvic sonograms. Basal LH levels were elevated (35 and 42 U/L), with normal FSH (7.9 and 7.8 U/L) and high testosterone levels (1330 and 1660 ng/dl). The molecular analysis identified a missense mutation in exon 5 of AR gene that changed a proline to an alanine at position 766 of the protein. Proline 766 is a highly conserved amino acid in the AR of several species and is located in the androgen binding domain.     

Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

Acute graft-versus-host disease (GVHD) that is resistant to therapy is a highly lethal complication of marrow transplantation. Inflammatory cytokines such as interleukin-1 (IL-1) may be critical mediators of this process. If so, specific inhibition of IL-1 activity with recombinant human IL-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1, may ameliorate acute GVHD. We performed an open-label, phase I/II trial to evaluate the safety and efficacy of IL-1Ra in 17 patients with steroid-resistant GVHD. The IL- 1Ra was administered as a 24-hour continuous infusion over 7 days. The dose was escalated in cohorts of patients from 400 to 3,200 mg/d. Acute GVHD was evaluated in each affected organ and as an overall grade. Stage-specific improvement of acute GVHD occurred in the skin (8 of 14, 57%), gut (9 of 11, 82%), and liver (2 of 11, 18%). Overall, acute GVHD improved by at least one grade in 10 of 16 (63%) patients. Response to therapy was associated with a reduction of tumor necrosis factor-alpha (TNF-alpha) mRNA levels in blood mononuclear cells (P = .001). The only toxicity attributable to IL-1Ra was reversible transaminase elevation in two patients. Inhibition of IL-1 activity with IL-1Ra is safe and has demonstrable efficacy in acute GVHD that failed to respond to conventional treatment. These data provide further evidence that IL-1 is a mediator of GVHD.     

Short stature caused by SHOX gene haploinsufficiency: from diagnosis to treatment

Studies involving patients with short stature and partial deletion of sex chromosomes identified SHOX gene in the pseudoautosomal region of the X and Y chromosomes. SHOX haploinsufficiency is an important cause of short stature in a diversity of clinical conditions. It explains 2/3 of short stature observed in Turner syndrome (TS) patients. Heterozygous mutations in SHOX are observed in 77% of patients with Leri-Weill dyschondrosteosis, a common dominant inherited skeletal dysplasia and in 3% of children with idiopathic short stature, indicating that SHOX defects are the most frequent monogenetic cause of short stature. The sitting height/height ratio (SH/H) standard deviation score is a simple way to assess body proportions and together with a careful exam of other family members, effectively selected a group of patients that presented a high frequency of SHOX mutations. Growth hormone treatment of short stature due to TS is well established and considering the common etiology of short stature in patients with isolated defects of SHOX gene, this treatment is also proposed for these patients. Here, we review clinical, molecular and therapeutic aspects of SHOX haploinsufficiency.     

Polymorphisms identified in the upstream core polyadenylation signal of IGF1 gene exon 6 do not cause pre- and postnatal growth impairment

BACKGROUND: Few children born small for gestational age (SGA) with IGF1 mutations have been reported. One of these patients presented a mutation at 3' untranslated region (UTR) at exon 6, probably affecting the polyadenylation process. OBJECTIVE: The objective of the study was to sequence the IGF1 gene of children born SGA. PATIENTS AND METHODS: IGF1 (exons 1-6) was directly sequenced in 53 SGA children without catch-up growth. Allelic variant frequency of the identified IGF1 polymorphisms was assessed in a total of 145 SGA children and in 180 controls born with adequate weight and length and adult height sd score greater than -2. RESULTS: No mutations were identified in the IGF1 coding regions in SGA children. In contrast, six allelic variants were identified in the upstream core polyadenylation signal located in IGF1 3' UTR at exon 6. The frequency of the different allelic variants was similar in SGA children and controls. It is noteworthy that the same allelic variant, previously described as causing severe IGF1 deficiency, was also observed in homozygous (n = 4) and heterozygous state (n = 6) in normal height controls, corresponding to 4% of studied alleles. The three most frequently identified allelic variants of IGF1 3' UTR showed no effect on height sd score of adult controls as well as on birth characteristics in SGA children. CONCLUSION: The polymorphisms identified in the upstream core polyadenylation signal at IGF1 exon 6 do not cause IGF1 deficiency as well as pre- and postnatal growth impairment, in contrast to previously reported data.