The volumetric bone density and cortical thickness in adult patients affected by osteogenesis imperfecta.

In patients with osteogenesis imperfecta (OI), a disease characterized by abnormal bone fragility, bone mineral density (BMD) was found to be relatively preserved. Quantitative computed tomography (QCT) is the only available method for directly measuring in vivo both volumetric density and the cross-sectional area. Here we report the data from dual-energy X-ray absorptiometry DXA (spine and hip) and peripheral (pQCT) (ultradistal and proximal radius) measurement of 27 adult patients affected by OI, mostly of type I, compared with a group of healthy persons. In the patients with OI, areal BMD values at both femoral neck and lumbar spine were considerably lower than in control subjects (-32 and -36%, respectively; p<0.001 for body weight and height adjusted values). pQCT volumetric density at the ultradistal radius was 19% lower than in control subjects and this difference rose to 32% for purely cancellous bone tissue. The whole bone cross-sectional area of ultradistal radius, as measured by pQCT, was superimposable to normal. At the proximal radius, both cross-sectional area and cortical area, together with Bending Breaking Resistance Index (BBRI), were significantly lower in OI (-23; -22; -32% respectively; p<0.001 for body weight and height adjusted values), but cortical volumetric density was even slightly higher in the OI group than in control subjects. In conclusion, it appears that the most obvious defect in adults with OI is the inability to acquire an adequate thickness of the cortices of long bone and to achieve or maintain normal trabecular density.     

Screening for Anti-Human T-Lymphotropic Virus Antibody in Blood Donors and Polytransfused Patients in Apulia (Italy)

A stringent procedure for the diagnosis of human T-lymphotropic virus (HTLV) infection was applied to 1,732 volunteer blood donors, 401 patients with various hematological disorders and 78 individuals at high risk for HIV infection. It consisted of a viral lysate-based screening assay (Abbott Laboratories, North Chicago, Ill., USA), and two confirmatory assays (Western blot and radioimmunoprecipitation assay). A confirmed positive sample had to react with at least two different HTLV gene products. Evidence of HTLV infection was not found in either blood donors or patients with hematological disorders. In fact, HTLV infection was only observed in 10 intravenous drug abusers or their sexual partners. Contrary to previous reports that claimed HTLV seroprevalences of between 0.3 and 8% in blood donors from Apulia (Italy), our data suggest that infection with this virus is principally restricted to intravenous drug abusers.     

Identification of New Natural CphA Metallo-β-Lactamases CphA4 and CphA5 in Aeromonas veronii and Aeromonas hydrophila Isolates from Municipal Sewage in Central Italy

Two new natural CphA metallo-β-lactamases, the CphA4 and CphA5 enzymes, were identified in water samples from municipal sewage in central Italy. Compared to CphA, the CphA4 and CphA5 enzymes showed numerous point mutations. These enzymes have a narrow spectrum of substrates focused on carbapenems only. CphA5 showed k_cat values about 40-, 12-, and 97-fold higher than those observed for CphA4 versus imipenem, ertapenem, and biapenem, respectively.     

Smith-Magenis syndrome and growth hormone deficiency

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome including physical and neurobehavioural features. The disease is commonly associated with a ca. 3.7 Mb interstitial deletion of chromosome 17p11.2, while a 1.1 Mb critical region has been identified, containing about 20 genes expressed in multiple tissues. Haploinsufficiency of one of them, RAI1, seems to be responsible for the neurobehavioural, craniofacial and otolaryngological features of the syndrome, but not for short stature, commonly seen in SMS patients with chromosome deletion, implying the role of other genes in the 17p11.2 region. Growth failure is a final result of several different mechanisms involving decreased growth hormone (GH) production, reduced tissue response to GH, or impaired activity of epistatic factors. To our knowledge, the association of GH deficiency with SMS has never been reported and rarely investigated, despite the very short stature of SMS patients. We describe a girl with a full SMS phenotype and a typical 3.7 Mb deletion of 17p11.2 who also has GH deficiency. After starting replacement therapy, growth has significantly improved, her stature being now above both the 10th percentile and her genetic target. Conclusion:we suggest that an investigation of both growth hormone secretion and function is carried out in patients with Smith-Magenis syndrome and 17p11.2 deletion.Abbreviations FISH fluorescent in situ hybridisation - GH growth hormone - SMS Smith-Magenis syndrome     

Intravenous intermittent neridronate in the treatment of postmenopausal osteoporosis

Bisphosphonates have been used with success in the treatment of osteoporosis, but oral therapy often lacks compliance. Here we report the results of clinical trial with aminobisphosphonate neridronate administered intravenously (i.v.). The study included 78 postmenopausal women with spine bone mineral density (BMD) at least -2.5 SD below peak. Patients were randomized to receive for 2 years either 50 mg i.v. neridronate bimonthly and 500 mg calcium plus 400 U vitamin D supplements daily (n=39) or calcium-vitamin D supplements alone (control group, n=39). Treatment was continued over 2 years with an additional 1 year follow-up of calcium-vitamin D supplements alone. Neridronate was well tolerated with the appearance of typical clinical signs of an acute phase reaction in only 3 of the patients after the first infusion. In the control group no significant changes in BMD or bone markers were observed. In the neridronate group BMD rose progressively at the spine rose up to 7.4% +/- 6.1% (SD) and at the femoral neck up to 5.8% +/- 8.2% (SD) at the end of the second year. In the succeeding follow-up these gains were maintained at both skeletal sites. Serum bone alkaline phosphatase (bone ALP) and serum type I collagen C-telopeptide (s-CTX) significantly decreased within 2 months. The bone ALP values reached a -35% plateau after 6 months, while s-CTX attained the lowest mean value (-47%) only by the end of the treatment with neridronate. Both bone markers returned almost to baseline values 1 year after treatment discontinuation. Treatment of postmenopausal osteoporosis with 50 mg i.v. neridronate bimonthly results in clinically relevant increases in BMD, among the largest so far observed with any other bisphosphonate.     

STI 571 inhibition effect on KITAsn822Lys-mediated signal transduction cascade

OBJECTIVE: Alterations in growth factor signaling pathways may be a frequent collaborating event in AML1-ETO-mediated leukemogenesis. Gain-of-function KIT receptor mutations have been reported in adult AML patients, especially those with core binding factor leukemia (CBFL). We have previously reported a new gain-of-function KIT(Asn822Lys) mutation that is constitutively expressed in the Kasumi-1 CBFL cell line, and has recently been described in two childhood AML patients. To explore the molecular basis of the effects of this mutation in the appropriate context of hemopoietic dysregulation, we investigated KIT downstream signaling in the Kasumi-1 cell line by means of STI 571 (Imatinib, Gleevec) pharmacological inhibition. MATERIALS AND METHODS: We investigated KIT(Asn822Lys) mutant-initiated signaling in Kasumi-1 cell line, and characterized the inhibitory effect of the STI 571 protein tyrosine kinase inhibitor on downstream signaling. RESULTS: The use of STI 571-mediated inhibition impaired the tyrosine phosphorylation of KIT(Asn822Lys) and its association with the p85 subunit of phosphatidylinositol 3'-kinase (p85PI3K). The downstream constitutive phosphorylation of JNK1/2 and STAT3 was also significantly inhibited, but STI 571 had no effect on the constitutive activation of Akt, thus suggesting that it is due to other signaling in Kasumi-1 cells. STI 571 inhibited the KIT-mediated proliferation of Kasumi-1 cells in a dose-dependent manner. CONCLUSIONS: These findings show the role of PI3K in KIT(Asn822Lys)-mediated constitutive activation through the Akt-independent downstream signaling pathway of JNK, and also demonstrate the mutant's susceptibility to STI 571, which may therefore have therapeutic potential in CBFL patients with susceptible KIT mutations.