Novel mutations in the SH3BP2 gene associated with sporadic central giant cell lesions and cherubism

Central giant cell lesion (CGCL) is a reactive bone lesion that occurs mainly in the mandible, characterized by the multinucleated osteoclast-like giant cells in a background of oval to spindle-shaped mononuclear cells. The etiology is unknown and occurs more commonly in young adults. Cherubism, a rare disease found predominantly in females has histologic characteristics indistinguishable from those of CGCL and is caused by mutations mostly present in exon 9 of the SH3BP2 gene. In this study, we investigated four cases of CGCL and one case of cherubism. DNA was extracted from peripheral blood and tumor tissue and all coding and flanking regions of the SH3BP2 amplified by PCR and directly sequenced to identify underlying mutations. Two novel mutations were found; a heterozygous missense mutation c.1442A>T (Q481L) in exon 11 in one sporadic case of CGCL and a heterozygous germline and tumor tissue missense mutation c.320C>T (T107M) in exon 4 in one patient with cherubism. These findings open a new window to investigate the possible relationship between the pathogenesis of the cherubism and CGCL.     

The influence of sera, follicular fluids and seminal plasma on human sperm-zona pellucida binding

The purpose of this study was to assess the influence of male, female and fetal cord sera, follicular fluid, and seminal plasma on human sperm-zona pellucida binding, using the hemizona assay. Steroids, gonadotrophins, growth hormone and prolactin concentrations in follicular fluid and sera were also analysed. The influence of follicular fluid (10 or 50%, v/v) and sera (10%) on sperm-zona pellucida binding was investigated by supplementing the sperm processing medium as well as the sperm-hemizona incubation medium. Different seminal plasma concentrations (1 or 10%) were added to the sperm-hemizona incubation medium. Supplementation with 10% day 3 donor serum was used as a control throughout experimentation. Although supplementation with male sera and fetal cord serum exerted a stimulatory effect (36 and 90% respectively; P < 0.029) on sperm-zona pellucida binding, hemizona indices obtained with addition of male sera, fetal cord serum and sera obtained from sub-fertile in-vitro fertilization (IVF) patients on day 12 of their menstrual cycle did not differ significantly (P > 0.05). Final progesterone concentrations in sperm-zona pellucida incubation media (10% follicular fluid supplementation), which ranged from 0.788 to 3.85 microg/ml, enhanced sperm binding to the zonae by >100% (P < 0.02). The utilization of follicular fluid (10%) as a natural physiological stimulus to enhance sperm-zona pellucida binding in an IVF setting is recommended. The presence of seminal plasma in the spermzona pellucida incubation media showed no beneficial effect on the binding ability of sperm, and can be viewed as an unfavourable substance in the proximity of the oocyte.      

The thoracic aorta studied by MR imaging

Thirty-three patients with a variety of disorders of the thoracic aorta (aneurysm, dissection, Marfan syndrome, coarctation/pseudocoarctation, L-transposition, and Takayasu disease) were evaluated with magnetic resonance (MR) imaging. MR imaging delineated the presence and extent of thoracic aortic aneurysms and showed the relationship of the aneurysm to arch vessels; it also demonstrated intimal flaps and individual lumina in types A and B aortic dissection. Dilation of the ascending aorta in Marfan syndrome and focal narrowing of the aorta in coarctation were well visualized. The anteroposterior and side-to-side relationships of the aorta and pulmonary artery in L-transposition were demonstrated, as were aortic wall thickening and branch vessel narrowing in Takayasu arteritis. Initial experience suggests that MR imaging may provide a noninvasive method for evaluating thoracic aortic disease. Limitations include inferior spatial resolution, occasional difficulty in imaging the entire region of interest in one section, lack of signal from calcifications, and inability to monitor critically ill patients.     

Adrenocorticoid receptor binding in the rat hippocampus: strain-dependent covariations with arousal and habituation to novelty

In order to investigate whether the genotype-dependent behaviour of the Naples high-(NHE) and low-excitability (NLE) rat strains was modulated by differences in the capacity of hippocampal adrenocorticoid receptors, a correlative analysis was made among behavioural scores from exposure to a Làt-maze and in vitro [3H]corticosterone hippocampal binding capacity in these rats and in their random-bred controls (NRB). As previously shown, NHE/NLE-rats differed markedly upon forced exposure to the maze, with the NRB group occupying an intermediate position. No differences were found in maximal binding capacity (Bmax) and dissociation constant (Kd), nor in the individual maximal binding capacity (IMBC) between the two strains, while both showed lower IMBC than NRB-rats. These results tend to exclude that the genetic differences in the behaviour of NHE/NLE-rats are due to distinct patterns in the adrenocorticoid binding capacity in the hippocampus (HPC). Moreover, the intrastrain correlative analysis among IMBC (in the whole HPC and in its dorsal and ventral portion) and the behavioural scores showed that (1) motor and emotional correlates of 'arousal' to novelty were positively correlated in NLE and negatively in NHE-, but not in NRB-rats; (2) a consistent correlation was found with the intertrial activity decrement (long-term habituation), which was negative in both strains, and it was positive in NRB-rats. These complex co-variations are envisioned as possibly due to the differential modulatory components of the activation and inhibition of novelty-induced arousal response. However, our findings support the hypothesized involvement of the HPC, where adrenocorticoid receptors are selectively concentrated, in the modulation of some adaptive behavioural responses.     

A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group

The development of antibodies to factor VIII (inhibitors) in response to clotting-factor concentrates administration in hemophilia is common during the first few years of treatment but rare in multitransfused patients. We have investigated the possible association of a recently introduced factor VIII concentrate (Factor VIII CPS-P) in The Netherlands with the occurrence of inhibitors. To this effect, we conducted two studies. First, we performed a national multicenter study in which clinical information and inhibitor test results were obtained for 447 hemophilia A patients over the period 1988 through 1991. Secondly, for a baseline comparison we estimated the frequency of inhibitor development in a closely followed cohort of 144 patients, from 1984 through 1989. Before the introduction of Factor VIII CPS-P, the incidence of new inhibitors was 4.4/1,000 patient-years in the national study from March 1988 through May 1990, and 3.9/1,000 patient- years in the cohort followed from 1984 through 1989. These figures are similar to the incidence of new inhibitors that was found in a large cohort of patients in the United States followed in the 1970s. In the period that the new concentrate Factor VIII CPS-P was on the market, from June 1990 through November 1991, 11 clinically relevant inhibitors were detected, which yielded an incidence over this interval of 20.1/1,000 patient-years, a 4.5-fold increase compared with the previous interval (C195: 1.4 to 14.3). Nine of these 11 patients had in their lifetime received over 250 infusions with factor VIII preparations. whereas all of the inhibitors detected in the previous time interval, and all of the 24 inhibitor patients described in the US study, had received less than 250 infusions in their lifetime. All patients who developed inhibitors after June 1990 had been exposed to Factor VIII CPS-P, whereas only 75% of the patients who did not develop an inhibitor had been exposed to this product. In a prospective extension of the study, with a second inhibitor measurement after 3 months, we found that one additional inhibitor had developed during 52.5 patient-years of Factor VIII CPS-P use. In conclusion, there has been a sudden increase in the frequency of inhibitor patients, for a large part among multitransfused patients. It seems more than likely that this increase is associated with the introduction of a new factor VIII concentrate in The Netherlands.(ABSTRACT TRUNCATED AT 400 WORDS)     

Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate

The incidence of neutralizing isoantibody formation to infused factor VIII in a cohort of 67 hemophilia A patients, born between January 1, 1971 and April 30, 1990, who had been treated exclusively with lyophilized cryoprecipitate, was 6% (5.3 per 1,000 patient years of observation). The age-dependent cumulative risk was 4.6% at 4 years of age and 6.7% at 8 years of age. Recent reports in patients treated with a variety of more pure concentrates show a much higher incidence of inhibitor formation and tend to be used as a reference when new concentrates are introduced. We believe that a patient group, such as the one studied here, is a more suitable reference population because these patients have been exclusively treated with a single factor VIII preparation.     

Craniosynostosis in X-linked hypophosphataemic rickets

A report of three cases of craniosynostosis in X-linked hypophosphataemic rickets (XLH) is presented. The literature is reviewed, suggesting that craniosynostosis is relatively common in XLH and that boys may be more at risk than girls. It is recommended that radiological screening be offered to all patients with XLH.