Chemical synthesis, characterisation and biological evaluation of furanic-estradiol derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1

Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a series of epoxide and furanic E2 derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1. An intermediate epoxide was first obtained and then reduced to give a furanic steroid, which allowed us to introduce a molecular diversity like alcohol, bromide, ester, acid and amide. The inhibition of the transformation of [(14)C]-E1 (100 nM) into [(14)C]-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17β-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 μM. All furanic compounds showed a lower 17β-HSD1 inhibitory potency in intact T47-D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide, which gave 62% and 90% of inhibition of the [(14)C]-E1 (60 nM) into [(14)C]-E2 transformation at 1 and 10 μM, respectively.     

Final adult height in children with Prader-Willi syndrome with and without human growth hormone treatment

Short stature is characteristic of children with Prader-Willi syndrome (PWS). While previous studies have demonstrated acceleration of linear height velocity with growth hormone (GH) treatment, the long-term benefit on final adult height (AH) has not been reported. The objective of this study was to compare AH attained in PWS subjects with and without GH treatment. We reviewed the records of 21 children (aged 8.3 +/- 2.7 years) with PWS and confirmed GH deficiency that attained AH after receiving human GH treatment (0.25 +/- 0.06 mg/kg/week) for a period of 7.9 +/- 1.7 years. A group of 39 non-GH-treated adults with matched initial height standard deviation score (SDS) at age 6.8 +/- 1.3 years was used as control. In the GH-treated group the mean initial height and AH-SDS was -1.9 +/- 1.7 and -0.3 +/- 1.2 respectively (P < 0.0001), whereas the mean initial and AH-SDS in the control group was -1.9 +/- 1.3 and -3.1 +/- 1 respectively (P < 0.0001). Scoliosis was seen in 43% and 39% in the GH-treated and control group respectively. Premature adrenarche (PA) was noticed in 57% of GH-treated group. Six subjects in the control group but none of the GH-treated subjects developed type 2 diabetes mellitus. Our data show that administration of GH to children with PWS restores linear growth and final AH without significant adverse effects other than PA. Further studies will be necessary to determine related morbidity and mortality in individuals with PWS that reached final AH with or without GH treatment.     

Corticosteroids usage in pediatric liver transplantation: To be or not to be!

Abstract:  The theoretical risks of early SW, <3 months post-LT, and complete elimination (steroid-free LT) lie in mainly three areas, namely the risks of AGR, CGR, and the development of d-AIH that has been described in SW post-LT in children. These should be balanced against the benefits of early SW mainly manifested as effects on growth post-LT. In this paper, we focused on the clinical trials that included CS therapy risks and benefits in pediatric LT. Focusing mainly on CGR and d-AIH as risks, and the beneficial effects on growth post-LT with either low-dose CS, SW, or steroid-free regimens. Main conclusions from comparing a large number of studies are: early SW or elimination from immunosuppression protocols was neither harmful to the patient nor to the graft survival rate in the short term, the overall impression is that steroids negatively affect growth in LT recipients when used in high doses and prolonged course, and that development of d-AIH is not associated with CS therapy with evidence that chronic low dose steroids post-LT have no preventative role against d-AIH.     

A study of neonatal morbidity and mortality at Damanhour Teaching Hospital Newborn Unit

Newborns in Behira governorate represented 2.5% of total Behira population in 2000. In Damanhour teaching hospital 4040 live births were delivered during one year from 1st January 1995 to 31st December 1995. During this period an observational study of morbidity and mortality of the newborn unit (NBU) attendants was performed. The total number of admitted neonates to the newborn unit were 557, of those 307 were borne in hospital (representing 7.6% of total hospital deliveries) and 250 were admitted from outside the hospital. The number of eligible neonates for the study were 544, they spent 2355 days in the unit, thirteen neonates were excluded from the analysis. The low birth weight (< 2500 gm) were 218 (40% of studied cases). According to Dubowitz score, Infants were classified as appropriate for gestational age (AGA) 60.7%, small for gestational age (SGA) 27.6% and large for gestational age (LGA) 11.8%. Neonates with birth weight < 1500 gm and gestational age < 28 weeks had the worst prognosis with a mortality rate of 60.3% and 65.1% respectively. All neonates had 738 morbid conditions, the major causes were prematurity 262 (35.5%), respiratory distress (RD) 200 (27%) hyperbilirubinaemia 115 (15.6%) and sepsis 58 (7.9%). Most of the cases (73.9%) were admitted on the day of birth. The mortality rate was 28.5%. The leading causes of mortality were, RD ( 34.8% of all deaths), prematurity (32.9%) and sepsis (15.5%). Neonatal convulsions and congenital anomalies had highest case fatality rates (50% for each). Most of deaths (51%) occurred on the first day of admission. "The early results of this work was presented at the 6th international conference of the General Organization of "Teaching Hospitals and Institutes (GOTHI) "Health Services.....Present and future" 7-9 November 2001".     

Regression of CD8+ pseudolymphoma after HIV antiviral triple therapy

To our knowledge, we report the first case of improvement of HIV-associated cutaneous CD8(+) pseudolymphoma with highly active antiretroviral therapy. This favors the hypothesis of a reactive cutaneous infiltration by HIV-specific cytotoxic T cells in this disease.     

Uncoupling activation-induced modulation of CD16 and CD69 in CD56+ cells during AIDS

The immune system of HIV+ patients is chronically activated, which has been associated with a detrimental effect on both innate and acquired immunity during AIDS. We analyzed the expression and modulation of the triggering markers CD69 and CD16 in CD56+ cells from 18 asymptomatic HIV+ individuals and 8 AIDS patients, compared with 21 seronegative subjects. We observed a diminished PMA-induced CD16 downregulation in AIDS patients (p<0.01), associated with low numbers of CD4+ cells (p<0.02). Furthermore, an enhanced unstimulated expression of CD69 in asymptomatic HIV+ patients (p<0.05) was shown. AIDS patients could not efficiently upregulate PHA-dependent CD69 expression (p<0.05), which correlated with low CD4+ counts (p< 0.05). These abnormalities in CD16 and CD69 modulation were recorded in patients under highly active antiretroviral therapy (HAART). Our results demonstrate an altered modulation of two functionally relevant receptors in CD56+ cells from AIDS patients, contributing to our understanding of the immunopathogeny of NK cell dysfunction during disease progression.     

Posterior reversible encephalopathy syndrome revealing Takayasu's arteritis in a child

Posterior Reversible Encephalopathy Syndrome (PRES) is a rare complication of Takayasu''s Arteritis. We report the case of an 11-year-old girl who presented with a tonic-clonic seizure and loss of consciousness, without fever. Imaging revealed characteristic white matter edema of the occipital and parietal lobes, in keeping with PRES. Further imaging demonstrated right renal artery stenosis and wall thickening of the abdominal aorta. The combination of hypertension, the discrepancy of blood pressure recordings between upper limbs, and imaging abnormalities of the aorta and the left renal artery led to the diagnosis of PRES secondary to Takayasu''s Arteritis. Treatment with oral corticosteroids, azathioprine, amlodipine, and propranolol resulted in the complete resolution of the patient''s symptoms and imaging abnormalities.     

The nonresponse to hepatitis B vaccination is associated with impaired lymphocyte activation

Nonresponsiveness against hepatitis B vaccination has been described in 4-10% of immunized subjects. We have explored the specific cell response to hepatitis B surface antigen by analyzing: PBMC proliferation, cytokine production (Th1, Th2 profiles, and TGF-beta), and activation molecules on Th cells. A poor proliferative response was demonstrated in nonresponders (P < 0.05). T cells from responders produced all tested cytokines (P < 0.01), in contrast with nonresponders subjects (P < 0.05). Expression of CD69 and CD25 was diminished in T cells from nonresponders (P < 0.01). A reduced expression of CD40L was also detected in T cells from nonresponders (P < 0.01). An elevated correlation coefficient was observed between CD40L on CD4+ cells and antibody production. These results suggest an overall inability of T cells to be activated which could be consistent with potential differences in antigen presentation. In conclusion, our results suggest that an altered Th response may be a consequence of inappropriate early activation events.     

The intrathoracic kidney: should we fix it?

BackgroundIntrathoracic kidney is a rare congenital anomaly, with only 13 cases reported in the pediatric age group over the past 25 years. The relevant literature is limited to individual case reports or small case series with no follow-up data. Both operative and nonoperative management has been advocated. We report our experience in the management of children with an intrathoracic kidney as well as the efficacy of nonoperative management in select patients.MethodsFive cases of intrathoracic kidney were collected prospectively since 1992 and carefully followed up long term.ResultsTwo children presented with acute respiratory distress and underwent right diaphragmatic hernia repair and nephropexy. Incidental diagnosis of a left intrathoracic kidney was made in 3 children. Long-term follow-up has demonstrated normal function and development of these kidneys in all 5 children with no late bowel herniation in the nonoperative group.ConclusionIntrathoracic kidney associated with bowel in the chest should undergo standard repair and nephropexy. An isolated intrathoracic kidney without evidence of bowel herniation can safely be observed. This is the largest pediatric series of intrathoracic kidney as well as the first to document the efficacy of nonoperative management with long-term follow-up.