A novel missense mutation (I344K) in the SPG4gene in a Korean family with autosomal-dominant hereditary spastic paraplegia

 Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower extremities. Among eight loci linked with autosomal-dominant (AD)-HSP, the SPG4 locus on chromosome 2p22 accounts for about 40% of all patients. Recently, mutations in a new member of the AAA protein family, called spastin, have been identified as responsible for SPG4-linked AD-HSP. Here, we describe a novel missense mutation (c.1031T>A; I344K) in exon 7 of the SPG4 gene identified in a Korean family with typical clinical features of pure AD-HSP. The mutation affects the third amino acid of the highly conserved AAA cassette domain, which is the most fore part of the domain altered by a missense mutation reported so far. Clinical presentations of affected individuals carrying the I344K mutation were not different from those of pure AD-HSP with SPG4 mutations reported previously. However, it is noteworthy that neither urinary dysfunction nor involvement of upper extremities was noticed in this family. To our knowledge, this is the first report of genetically confirmed AD-HSP in Korea. Received: February 20, 2002 / Accepted: May 21, 2002     

Autologous stem cell transplantation in the treatment of refractory rheumatoid arthritis

The concept of using high-dose immunosuppressive treatment (HDIT) with autologous stem cell transplantation (ASCT) to treat patients with refractory rheumatoid arthritis has been provided by animal studies and anecdotal case reports. Over the past five years, an increasing number of patients with refractory rheumatoid arthritis have received HDIT with ASCT as an adjunct to intense immunosuppression. Here, we present a case of refractory rheumatoid arthritis in a 54-yr-old woman using HDIT with ASCT. Peripheral blood stem cells were mobilized with cyclophosphamide (4 g/m(2)) followed by G-CSF (5 microg/kg/day). Leukapheresis continued daily until the number of harvested progenitor cells reached 2 x 10(6) CD34+ cells/kg after CliniMax CD34+ positive selection. For HDIT, high-dose cyclophosphamide (total dose 200 mg/kg) and antithymocyte globulin (total dose 90 mg/kg) were administered and CD34+ cells were infused 24 hr after HDIT. The patient tolerated the treatment well but experienced an episode of neutropenic fever. She achieved an early dramatic improvement of joint symptoms during therapy. Fifty percent of improvement of rheumatoid arthritis by the American College of Rheumatology (ACR 50) preliminary definition was fulfilled during the 6 months following ASCT. Although further long-term follow-up is required, the patient's activity of arthritis has been stable since receiving HDIT with ASCT.     

In vitro biocompatibility assessment of sulfonated polyrotaxane-immobilized polyurethane surfaces

Sulfonated polyrotaxanes (PRx-SO(3)'s), in which sulfonated alpha-cyclodextrins (alpha-CDs) were threaded onto the poly(ethylene glycol) (PEG) segments in a PEG-b-poly(propylene glycol) (PPG)-b-PEG triblock copolymer (Pluronic) capped with benzyloxycarbonyl (Z)-L-phenylalanine (Z-L-Phe), were prepared as a novel surface-modifying biomaterial. Surface modification of the polyurethane (PU) was carried out by blending the PRx-SO(3)'s with a PU solution, followed by solution casting. The incorporated PRx-SO(3)'s led to the enhanced hydrophilicity by changing the surface properties of the PU matrix. Modified PUs showed the stable entrapment of the PRx-SO(3)'s with little extraction into water and enhanced mechanical properties after exposure to water compared to the PU control. The incorporated PRx-SO(3)'s repelled the proteins and kept them from closely approaching the surface areas, prevented platelet activation by thrombin, and effectively repelled bacteria. These results suggest that both the supramolecular structure of the polyrotaxanes and exposure of the sulfonated groups onto the surfaces contribute to these phenomena. Thus, surface modification with PRx-SO(3)'s is suggested to be useful for the fabrication of biocompatible medical devices.     

Births of normal daughters after MicroSort sperm separation and intrauterine insemination, in-vitro fertilization, or intracytoplasmic sperm injection

The world's first deliveries of normal babies after use of flow cytometric separated human sperm cells (MicroSort) for preconception gender selection are reported. Offspring were of the desired female gender in 92.9% of the pregnancies. Most of these pregnancies and births were achieved after simple intrauterine insemination.      

Compact and accurate linear and nonlinear autoregressive moving average model parameter estimation using Laguerre functions

A linear and nonlinear autoregressive moving average (ARMA) identification algorithm is developed for modeling time series data. The algorithm uses Laguerre expansion of kernals (LEK) to estimate Volterra-Wiener kernals. However, instead of estimating linear and nonlinear system dynamics via moving average models, as is the case for the Volterra-Wiener analysis, we propose an ARMA model-based approach. The proposed algorithm is essentially the same as LEK, but this algorithm is extended to include past values of the ouput as well. Thus, all of the advantages associated with using the Laguerre function remain with our algorithm; but, by extending the algorithm to the linear and nonlinear ARMA model, a significant reduction in the number of Laguerre functions can be made, compared with the Volterra-Wiener approach. This translates into a more compact system representation and makes the physiological interpretation of higher order kernels easier. Furthermore, simulation results show better performance of the proposed approach in estimating the system dynamics than LEK in certain cases, and it remains effective in the presence of significant additive measurement noise.     

Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities

An RNA-binding motif (RBM) gene family has been identified on the human Y chromosome that maps to the same deletion interval as the 'azoospermia factor' (AZF). We have identified the homologous gene family (Rbm) on the mouse Y with a view to investigating the proposal that this gene family plays a role in spermatogenesis. At least 25 and probably >50 copies of Rbm are present on the mouse Y chromosome short arm located between Sry and the centromere. As in the human, a role in spermatogenesis is indicated by a germ cell-specific pattern of expression in the testis, but there are distinct differences in the pattern of expression between the two species. Mice carrying the deletion Yd1, that maps to the proximal Y short arm, are female due to a position effect resulting in non-expression of Sry ; sex-reversing such mice with an Sry transgene produces males with a high incidence of abnormal sperm, making this the third deletion interval on the mouse Y that affects some aspect of spermatogenesis. Most of the copies of Rbm map to this deletion interval, and the Yd1males have markedly reduced Rbm expression, suggesting that RBM deficiency may be responsible for, or contribute to, the abnormal sperm development. In man, deletion of the functional copies of RBM is associated with meiotic arrest rather than sperm anomalies; however, the different effects of deletion are consistent with the differences in expression between the two species.      

Differential expression of hypoxia inducible factor-1 alpha and tumor cell proliferation between squamous cell carcinomas and adenocarcinomas among operable non-small cell lung carcinomas

This study aimed to evaluate whether the elevated level of hypoxia-inducible factor-1alpha (HIF-1alpha) correlated with histologic types, angiogenesis, tumor cell proliferation, and clinical parameters in common non-small cell lung carcinomas (NSCLCs). We performed immunohistochemical stains using paraffin-embedded tissue blocks from 84 cases of operable NSCLC [No. of squamous cell carcinoma (SCC), 45; No. of adenocarcinoma (AC), 39]. HIF-1alpha expression was related with histologic types (66.7% in SCCs vs 20.5% in ACs, p<0.001), but not with lymph node status, tumor stage, vascular endothelial growth factor expression, microvessel density (MVD), and proliferating cell nuclear antigen (PCNA) index (p>0.05, respectively). As for the histologic types, MVD and PCNA index were significantly higher in SCCs than in ACs (p=0.009 and p=0.016, respectively). Among HIF-1alpha positive carcinomas, MVD was significantly higher in HIF-1alpha positive SCCs than in HIF-1alpha positive ACs (p=0.023). The overall survival curves were not associated with HIF-1alpha expression or any other histologic parameters (p>0.05). These findings suggest that HIF-1alpha expression in NSCLCs may play a differential role according to histologic types, but its prognostic significance is indeterminate.     

Relationships of lead, copper, zinc, and cadmium levels versus hematopoiesis and iron parameters in healthy adolescents

To investigate the relationships of trace element concentrations vs hematopoiesis and iron parameters, we measured lead, copper, zinc, cadmium, and ferritin levels in 251 healthy adolescents. Concentrations of trace metals were determined by atomic absorption spectrophotometry. There were no significant gender-related differences in serum copper or serum cadmium concentrations. However, blood lead and serum zinc levels were significantly higher in males than females (3.82+/- 1.24 and 118.4 +/- 43.7 microg/dl vs 2.86+/- 1.06 and 83.5+/- 35.2 microg/dl, p<0.05, respectively). Subjects with elevated lead and copper concentrations exhibited significantly higher leukocyte counts and significantly lower serum iron levels than those with decreased lead and copper concentrations, but no significant differences were observed in blood erythrocyte counts or hemoglobin levels between the 2 groups. Blood lead concentrations were 2-fold higher in male adolescents with leukocytes >9.1 x 10(3)/microl than in those with leukocytes <4.3 x 10(3)/microl (5.04+/- 1.67 microg/dl vs 2.51+/- 0.75 microg/dl, p<0.05). Leukocyte counts had significant correlations with blood lead (r=0.39, p<0.05) and serum copper (r=0.26, p<0.05) in males and zinc (r=0.28, p <0.05) in females. Serum iron levels were inversely correlated with blood lead and serum copper concentrations but were not correlated with serum zinc or cadmium levels. In short, blood lead and serum copper concentrations have important relationships to leukocyte counts and iron parameters in adolescents.