Aryl phosphate derivatives of bromo-methoxy-azidothymidine are dual-function spermicides with potent anti-human immunodeficiency virus

Detergent-based vaginal microbicides, in addition to their high contraceptive failure rates, cause mucosal erosion and local inflammation that might increase the risk of heterosexual human immunodeficiency virus (HIV) transmission. In a systematic effort to identify a microbicide contraceptive potentially capable of preventing the sexual transmission of HIV as well as providing fertility control, a series of novel aryl phosphate derivatives of 5-bromo-6-methoxy-3'-azido-3'-deoxythymidine (AZT; zidovudine) were synthesized and examined for dual anti-HIV and sperm-immobilizing activity (SIA). Whereas AZT displayed potent anti-HIV activity (IC50 = 0.006 microM) but lacked SIA (EC50 > 300 microM), two 5-bromo-6-methoxy-aryl phosphate derivatives of AZT, compounds WHI-05 and WHI-07, exhibited potent anti-HIV activity as well as SIA. The IC50 (HIV) and EC50 (SIA) values for WHI-07 were 439-fold and 13.5-fold lower, respectively, than those for the detergent-based virucidal spermicide, nonoxynol-9 (N-9). Sperm motion kinematics using computer-assisted sperm motion analysis combined with confocal laser scanning microscopy, high-resolution low-voltage scanning, and transmission electron microscopy demonstrated that both WHI-05 and WHI-07 cause a complete and irreversible loss of sperm motility in a concentration- and time-dependent fashion without concomitantly affecting the sperm acrosomal membrane integrity. In experiments designed to assess the fertilizing capacity of treated sperm, preincubation of sperm with either compound resulted in a concentration-dependent loss of the ability to adhere to and penetrate zona-free hamster eggs as well as inhibition of binding to human zona. WHI-07 applied intravaginally prior to artificial insemination of epididymal sperm drastically reduced fertility in hormonally primed CD-1 mice. Unlike the intravaginal application of N-9, repetitive intravaginal application of WHI-07 did not damage the vaginal epithelium or cause local inflammation. Structure-function relationship analyses showed that the addition of bromo-methoxy functional groups to AZT was essential for, and the aryl phosphate derivatization contributory to, the SIA of both compounds. Compounds WHI-05 and WHI-07 may be useful as dual-function vaginal contraceptives for women who are at high risk for acquiring HIV/acquired immunodeficiency virus syndrome by heterosexual vaginal transmission.     

Treatment of cutout of a lag screw of a dynamic hip screw in an intertrochanteric fracture

Sixteen consecutive patients with cutout of a lag screw of a dynamic hip screw fixation in an intertrochanteric fracture were treated with reinsertion of a lag screw, bone cement supplementation in the neck-trochanter, and subtrochanteric valgus osteotomy. Postoperatively, patients were permitted to ambulate with protected weight-bearing. Fourteen patients were followed-up for at least 1 year (median 2 years; range 1-3 years), and all had a solid union. The union period took a median of 5 months, with a range of 3-7 months. Usually, union of an intertrochanteric fracture was faster than that of subtrochanteric osteotomy (P < 0.01). There were no complications of wound infection, loss of reduction, cutout of a lag screw, or osteonecrosis of the femoral head. From clinical and theoretical considerations, we conclude that despite cutout of a lag screw of a dynamic hip screw fixation being difficult to treat, out technique still can provide an excellent outcome. Therefore, we strongly recommend its wide use.     

An analytic and accurate model for the threshold voltage of short channel MOSFETs in VLSI

Based on the two-dimensional Poisson equation, the surface potential distribution along the surface channel of a MOSFET has been analytically derived by assuming negligible source and drain junction depths and its minimum potential is then used to determine the threshold voltage. The existence of a minimum surface potential point along the channel of a MOSFET under an applied drain bias is consistent with the numerical results of the two-dimensional analysis. The effects of finite source and drain junction depths have been elegantly included by modifying the depletion capacitance under the gate and the resulted threshold voltage model has been compared to the results of the two-dimensional numerical analysis. It has been shown that excellent agreement between these results has been obtained for wide ranges of substrate doping, gate oxide thickness, channel length (< 1 μm), substrate bias, and drain voltage. Moreover, comparisons between the developed model and the existing experimental data have been made and good agreement has been obtained. The major advantages of the developed model are that no iterations and no adjustable fitting parameters are required. Therefore, this simple and accurate threshold voltage model will become a useful design tool for ultra short channel MOSFETs in future VLSI implementation.     

Role of controlled debonding along fiber/matrix interfaces in the strength and toughness of metal matrix composites

In metal matrix composites toughness is derived primarily from the plastic work of rupture of ductile matrix ligaments between the fractured fibers and from the plastic work of simple shear separation along steps connecting major fracture terraces. In the optimization of tensile strength in the longitudinal and transverse directions together with the respective works of fracture the most important factor is the control of the extent of debonding along interfaces between the fibers and the matrix, which develops locally in the course of deformation in a continuously changing mix of modes. In Al alloy matrix composites reinforced with Al₂O₃ fibers an effective means of controlling the key interface fracture toughness is through coarsening of Al₂Cu intermetallic interface precipitates which prescribe a ductile fracture separation layer. A combined experimental approach and micromechanical modeling, utilizing a specially tailored novel tension/shear: traction/separation law provides the means for further optimization of overall behavior. This revised version was published online in July 2006 with corrections to the Cover Date.     

A clinicopathologic study of mucinous gastric carcinoma including multivariate analysis

BACKGROUND: Mucinous gastric carcinoma (MGC) is a rare subtype of gastric adenocarcinoma, and its clinical and pathologic features are still controversial. To clarify the significance of this subtype of carcinoma, the authors conducted a case-control study to investigate the clinicopathologic characteristics of MGC and determine whether this mucin-producing histologic type is associated with a worse prognosis than other gastric carcinomas. METHODS: Twenty-two cases of MGC and 46 patients with nonmucinous gastric carcinoma (NGC) were included. Patients were evaluated on the basis of age, gender, tumor size, location, depth of tumor invasion, histologic differentiation, lymph node involvement, organ metastasis, stage at presentation, surgical curability, adjuvant chemotherapy and radiation therapy. To determine whether the MGC itself was an independent prognostic factor, a multivariate analysis was performed with the Cox proportional hazards model. RESULTS: The MGC patients were found to have larger tumors (P < 0.001), tumors more often located in the upper stomach (P < 0.05), more serosal invasion (P < 0.05), more lymph node involvement (P < 0.05), greater frequency of advanced stage disease (P < 0.01), and lower 5-year survival rates (P < 0.05) than NGC patients. There was no significant correlation between the subtypes of differentiation of MGC and other data, including the prognosis. Multivariate analysis showed that clinically important predictive factors were serosal invasion and disease stage at diagnosis. The mucinous histologic type itself was not an independent factor for poor prognosis. CONCLUSIONS: The overall survival rate for patients with MGC was worse than that for patients with NGC. The poor prognosis was correlated with more advanced stage at diagnosis and more frequent serosal invasion, not with the mucinous histologic type.     

Interactions between arginine-rich histones and deoxyribonucleic acids. II. Circular dichroism

Circular dichroism (CD) was used to investigate the conformations of arginine-rich histones, H3 (III or f3) and H4 (IV or f2a1), and DNA in the complexes prepared by four different methods: (A) NaCl gradient dialysis with urea; (B) NaCl gradient dialysis without urea; (C) direct mixing in 2.5 x 10(-4) M EDTA, pH 8.0; and (D) direct mixing in 0.01 M sodium phosphate, pH 7.0. Using the CD spectrum of native chromatin as a criterion to judge the closeness of a complex to its native state, it was observed that a complex made by direct mixing at low ionic strength (methods C and D) is better than the ones made by NaCl gradient dialysis with or without urea (methods A and B). It is explained as a result of lack of ordered secondary structures in histones due to the presence of urea in method A or due to nonspecific aggregation in NaCl without urea (method B). Compared with all the earlier reports in literature on the CD of histone-DNA complexes, the CD spectra of arginine-rich histone-DNA complexes prepared by methods C and D are closest to that of native chromatin both in shape and in amplitude. These results imply (a) that arginine-rich histones play an important role in maintaining the conformation of chromatin and (b) that the binding of these two histones to DNA prepared by methods C and D are close to that in native chromatin. Noticeable variation in conformation of free and bound histone and histone-bound DNA has also been observed in histone H3 with one or two cysteine residues, and in reduced or oxidized state even when the complexes were prepared and examined in the same condition. CD spectra of arginine-rich histones in 0.01 M phosphates, pH 7.0, indicate the presence of alpha-helix which could be responsible for a favorable binding of the less basic regions of these histones to DNA under this condition as demonstrated by thermal denaturation (Yu, S. .S, Li H. J., and Shih, T. Y. (1976), Bio-chemistry, the preceding paper in this issue). To preserve or generate alpha-helical structures in histones seems to be a critical step in reconstituting good histone-DNA complexes.     

Solid fuel combustion experiments in microgravity using a continuous fuel dispenser and related numerical simulations

The conventional way of determining the flammability characteristics of a material involves a number of tedious single-sample tests to distinguish flammable from non-flammable conditions. A novel test device and fuel configuration has been developed that permits multiple successive tests for indefinite lengths of thin solid materials. In this device, a spreading flame can be established and held at a fixed location in front of optimized diagnostics while continuous variations of test parameters are made. This device is especially well-suited to conducting experiments in space (e.g. aboard the International Space Station) where the limited resources of stowage, volume, and crew time pose major constraints. A prototype version of this device was tested successfully in both a normal gravity laboratory and during low-gravity aircraft trials. As part of this ongoing study of material flammability behavior, a numerical model of concurrent-flow flame spread is used to simulate the flame. Two and three-dimensional steady-state forms of the compressible Navier-Stokes equations with chemical reactions and gas and solid radiation are solved. The model is used to assist in the design of the test apparatus and to interpret the results of microgravity experiments. This paper describes details of the fuel testing device and planned experiment diagnostics. A special fuel, developed to optimize use of the special testing device, is described. Some results of the numerical flame spread model are presented to explain the three-dimensional nature of flames spreading in concurrent flow and to show how the model is used as an experiment design tool.     

Acquiring and incorporating state-dependent timing requirements

Some real-time systems are designed to deliver services to objects that are controlled by external sources. Their services must be delivered on a timely basis, and the system fails when some services are delivered too late. In general, the timing requirements of the system may change when the states of the objects monitored by the system change. Such a system may fail if the timing requirements which it is designed to meet are erroneous. It may underutilize resources and consequently be costly or unreliable if the requirements are too stringent. Hence, one must identify how changes in object states call for changes in system requirements and how these changes should be incorporated into the design and implementation of the system. This paper first describes a methodology to determine timing requirements and to take into account requirement changes at runtime. The method is based on several timing requirement determination schemes. Simulation data show that these schemes are effective for applications such as mobile IP hand-offs. The paper then discusses how to incorporate this methodology in the system architecture and in the development process.

Evaluation of the impact of fuel hydrocarbons and oxygenates on groundwater resources

The environmental behavior of fuel oxygenates (other than methyl tert-butyl ether [MTBE]) is poorly understood because few data have been systematically collected and analyzed. This study evaluated the potential for groundwater resource contamination by fuel hydrocarbons (FHCs) and oxygenates (e.g., tert-butyl alcohol [TBA], tertamyl methyl ether [TAME], diisopropyl ether [DIPE], ethyl tert-butyl ether [ETBE], and MTBE) by examining their occurrence, distribution, and spatial extent in groundwater beneath leaking underground fuel tank (LUFT) facilities, focusing on data collected from over 7200 monitoring wells in 868 LUFT sites from the greater Los Angeles, CA, region. Excluding the composite measure total petroleum hydrocarbons as gasoline (TPHG), TBA has the greatestsite maximum (geometric mean) groundwater concentration among the study analytes; therefore, its presence needs to be confirmed at LUFT sites so that specific cleanup strategies can be developed. The alternative ether oxygenates (DIPE, TAME, and ETBE) are less likely to be detected in groundwater beneath LUFT facilities in the area of California studied and when detected are present at lower dissolved concentrations than MTBE, benzene, or TBA. Groundwater plume length was used as an initial indicator of the threat of contamination to drinking water resources. Approximately 500 LUFT sites were randomly selected and analyzed. The results demonstrate MTBE to pose the greatest problem, followed by TBA and benzene. The alternative ether oxygenates were relatively localized and indicated lesser potential for groundwater resource contamination. However, all indications suggest the alternative ether oxygenates would pose groundwater contamination threats similar to MTBE if their scale of usage is expanded. Plume length data suggest that in the absence of a completely new design and construction of the underground storage tank (UST) system, an effective management strategy may involve placing greater emphasis on UST program for ensuring adequate enforcement and compliance with existing UST regulations.