Growth hormone deficiency in a child with Williams-Beuren syndrome. The response to growth hormone therapy

Pre- and postnatal growth retardation of unknown pathogenesis is a common clinical feature in patients with Williams-Beuren syndrome (WBS). However, growth hormone deficiency (GHD) has not been considered a major cause of growth retardation. There is only one patient in the literature with confirmed GHD who responded well to human growth hormone (hGH) therapy. We report a female infant with confirmed WBS who, through provocative testing, was found to have GHD and who responded satisfactorily to hGH therapy. Height SDS was -4.2 at the age of 12 months when hGH was initiated and increased to -0.8 at the age of 4.25 years. The pathogenesis of GHD in our patient is unclear. Nevertheless, the elevated levels of prolactin and the response of hGH to growth hormone releasing hormone (GHRH) administration are indicative of a hypothalamic rather than pituitary defect. In conclusion, GH deficiency might contribute to the growth failure in a number of patients with WBS and in such cases hGH therapy will most likely improve final height.     

Evidence that unsaturated fatty acids are potent inhibitors of renal UDP-glucuronosyltransferases (UGT): kinetic studies using human kidney cortical microsomes and recombinant UGT1A9 and UGT2B7

Renal ischaemia is associated with accumulation of fatty acids (FA) and mobilisation of arachidonic acid (AA). Given the capacity of UDP-glucuronosyltransferase (UGT) isoforms to metabolise both drugs and FA, we hypothesised that FA would inhibit renal drug glucuronidation. The effect of FA (C2:0-C20:5) on 4-methylumbelliferone (4-MU) glucuronidation was investigated using human kidney cortical microsomes (HKCM) and recombinant UGT1A9 and UGT2B7 as the enzyme sources. 4-MU glucuronidation exhibited Michaelis-Menten kinetics with HKCM (apparent K(m) (K(m)(app)) 20.3 microM), weak substrate inhibition with UGT1A9 (K(m)(app) 10.2 microM, K(si) 289.6 microM), and sigmoid kinetics with UGT2B7 (S(50)(app)440.6 microM) Similarly, biphasic UDP-glucuronic acid (UDPGA) kinetics were observed with HKCM (S(50) 354.3 microM) and UGT1A9 (S(50) 88.2 microM). In contrast, the Michaelis-Menten kinetics for UDPGA observed with UGT2B7 (K(m)(app) 493.2 microM) suggested that kinetic interactions with UGTs were specific to the xenobiotic substrate and the co-substrate (UDPGA). FA (C16:1-C20:5) significantly inhibited (25-93%) HKCM, UGT1A9 or UGT2B7 catalysed 4-MU glucuronidation. Although linoleic acid (LA) and AA were both competitive inhibitors of 4-MU glucuronidation by HKCM (K(i)(app) 6.34 and 0.15 microM, respectively), only LA was a competitive inhibitor of UGT1A9 (K(i)(app) 4.06 microM). In contrast, inhibition of UGT1A9 by AA exhibited atypical kinetics. These data indicate that LA and AA are potent inhibitors of 4-MU glucuronidation catalysed by human kidney UGTs and recombinant UGT1A9 and UGT2B7. It is conceivable therefore that during periods of renal ischaemia FA may impair renal drug glucuronidation thus compromising the protective capacity of the kidney against drug-induced nephrotoxicity.     

A novel E1A-E1B mutant adenovirus induces glioma regression in vivo

Malignant gliomas are the most frequently occurring primary brain tumors and are resistant to conventional therapy. Conditionally replicating adenoviruses are a novel strategy in glioma treatment. Clinical trials using E1B mutant adenoviruses have been reported recently and E1A mutant replication-competent adenoviruses are in advanced preclinical testing. Here we constructed a novel replication-selective adenovirus (CB1) incorporating a double deletion of a 24 bp Rb-binding region in the E1a gene, and a 903 bp deleted region in the E1b gene that abrogates the expression of a p53-binding E1B-55 kDa protein. CB1 exerted a potent anticancer effect in vitro in U-251 MG, U-373 MG, and D-54 MG human glioma cell lines, as assessed by qualitative and quantitative viability assays. Replication analyses demonstrated that CB1 replicates in vitro in human glioma cells. Importantly, CB1 acquired a highly attenuated replicative phenotype in both serum-starved and proliferating normal human astrocytes. In vivo experiments using intracranially implanted D-54 MG glioma xenografts in nude mice showed that a single dose of CB1 (1.5 x 10(8) PFU/tumor) significantly improved survival. Immunohistochemical analyses of expressed adenoviral proteins confirmed adenoviral replication within the tumors. The CB1 oncolytic adenovirus induces a potent antiglioma effect and could ultimately demonstrate clinical relevance and therapeutic utility.     

Immunomodulation of invasive fungal infections

Genetic and acquired (disease- or therapy- related) host immune factors increase the risk for IFIs. In addition to antifungal drug therapy, modulation of host defenses by the use of HGFs and IFN-gamma has been supported by extensive in vitro and in vivo preclinical data. Clinical studies on the prevention or the adjunctive therapy of IFIs in combination with antifungal agents are limited, however, and do not allow specific recommendations for their cost-effective use in most of the immunodeficient settings. There is an urgent need to push forward with well-structured, randomized clinical trials to determine optimal dose, duration, and timing for different combinations of immunotherapy and antifungal agents in high-risk patients.     

Trichosporon asahii: an unusual cause of invasive infection in neonates

Trichosporon asahii causes white piedra, an infection of hair shafts and onychomycosis in immunocompetent patients, as well as various localized or disseminated invasive infections in immunodeficient hosts. We describe a 26-week gestation 890-g vaginally delivered female neonate who had severe respiratory distress syndrome and on the sixth day of life developed Klebsiella pneumoniae sepsis. At the same time two blood cultures were positive for T. asahii. The neonate was also colonized with T. asahii in the pharynx and perineum. The infant was successfully treated with conventional amphotericin B.     

Application of denaturing gradient gel electrophoresis (DGGE) to screen for mutations of the human glucocorticoid receptor alpha gene (hGRalpha)

OBJECTIVES: In a previous publication, we had presented a sensitive method to detect mutations of the segment of the human glucocorticoid receptor alpha (hGRalpha) gene encoding the ligand binding domain (LBD) and part of the DNA binding domain (DBD) of hGRalpha, as several types of glucocorticoid resistance syndromes have been correlated with mutations in the respective nucleotide sequences. However, mutations affecting various regions covering the whole length of hGRalpha are increasingly reported in a variety of disease states. We now present an expanded screening methodology to detect mutations covering the whole length of hGRalpha. DESIGN AND METHODS: We developed a sensitive, simple screening PCR-DGGE method to detect mutations in the aminoterminal domain and DNA-binding domain of the hGRalpha. Wild type hGRalpha cDNA and mutant samples were included in the analysis to ensure the accuracy and sensitivity of the method. RESULTS: The PCR-DGGE method identified the mutant samples and discriminated them from wild type hGRalpha. CONCLUSIONS: The method described is accurate, sensitive, simple, cheap and fulfills the critera for a screening method which will be useful in delineating possible involvement of hGRalpha mutations in the aetiopathology of diseases correlated to derangements of glucocorticoid action.     

Esthesioneuroblastoma: the Northwestern University experience

OBJECTIVE: To review our experience with esthesioneuroblastoma, a rare malignancy of the head and neck. STUDY DESIGN: Retrospective review of Tumor Registry data. METHODS: We performed a computerized search of the Northwestern Memorial Hospital Tumor Registry database from 1981 to 2000. RESULTS: Sixteen patients with esthesioneuroblastoma were identified and analyzed. Their mean age was 42 years. Eleven of 16 patients (69%) had Kadish stage C; 8 patients (50%) had brain involvement at presentation. Craniofacial resection was performed in 13 patients (81%). Fourteen patients received either preoperative or postoperative therapy; radiation therapy was employed in 11 cases and chemotherapy in 4. The actuarial 5-year survival was 60%, and the actuarial 5-year disease-free survival was 33%, with a median follow-up of 4.3 years. Recurrences occurred at a median time of 11 months after diagnosis (2.5 mo-18 y). The first site of failure was locoregional alone in 10 of 12 patients who progressed, and in 6 patients involved the brain or the meninges. Two patients were successfully salvaged. Patients with high-grade tumors had a trend toward work survival. CONCLUSIONS: Esthesioneuroblastoma is a rare tumor that is potentially curable by surgical resection and radiation therapy. However, the rate of local failure is high, and late recurrences are not uncommon. The role of chemotherapy warrants further investigation.