Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia.

XIAP is a member of the inhibitors-of-apoptosis family of proteins, which inhibit caspases and block cell death, with prognostic importance in AML. Here we demonstrate that cytokines regulate the expression of XIAP in leukemic cell lines and primary AML blasts. Inhibition of phosphatidylinositol-3 kinase (PI3K) with LY294002 and of the mitogen-activated protein kinase (MAPK) cascade by PD98059 resulted in decreased XIAP levels (34+/-8.7 and 23+/-5.7%, respectively). We then generated OCI-AML3 cells with constitutively phosphorylated Akt (p473-Akt) by retroviral gene transfer. Neither these nor Akt inhibitor-treated OCI-AML3 cells showed changes in XIAP levels, suggesting that XIAP expression is regulated by PI3K downstream effectors other than Akt. The induction of XIAP expression by cytokines through PI3K/MAPK pathways is consistent with its role in cell survival. Exposure of leukemic cells to chemotherapeutic agents decreased XIAP protein levels by caspase-dependent XIAP cleavage. Targeting XIAP by XIAP antisense oligonucleotide resulted in downregulation of XIAP, activation of caspases and cell death, and sensitized HL-60 cells to Ara-C. Our results suggest that XIAP is regulated by cytokines through PI3K, and to a lesser degree through MAPK pathways. Selective downregulation of XIAP expression might be of therapeutic benefit to leukemic patients.     

Human papillomavirus, cytomegalovirus and herpes simplex virus infections for cervical cancer in Taiwan

Previously, we had reviewed 43 cases of invasive cancers, adenosquamous cell carcinoma and adenocarcinoma for HPV type infections. With the same cases we extended the investigation to cytomegalovirus (CMV) and herpes simplex virus (HSV) infections. Results show that the prevalence of CMV and HSV infections from these cases of cervical carcinoma was 67 and 76%, respectively, by polymerase chain reaction. The results of the analysis of the association of HPV, CMV and HSV with various clinical characteristics of cervical cancer patients indicated that the correlation between HSV infections and clinical stages of squamous carcinoma was marginally significant (P=0.068). HSV infections seemed to have a higher association with cell keratinization pattern as compared with the other two viral infections.     

Paracrine effects of hepatocyte growth factor/scatter factor on non-small-cell lung carcinoma cell lines.

We have studied the mitogenic, motogenic and morphogenic effects of hepatocyte growth factor (HGF), also known as scatter factor (SF), on 15 non-small-cell lung carcinoma (NSCLC) cell lines that have had their ras genotype determined. HGF/SF stimulated proliferation in only three cell lines and exerted no mitogenic activity on six lines. The growth of the remaining six lines was inhibited. The mitogenic effects were not related to the ras genotype of these cell lines, but the inhibitory effect was more commonly observed in cell lines with relatively high levels of Met/HGF receptor (HGFR) expression. HGF/SF induced or enhanced both scatter activity on monolayer culture and single-cell invasion in collagen gels in approximately half of these cell lines. Although the ras genotype of tumour cells did not influence the HGF/SF-induced motogenic activity, cell lines with the mutant ras genotype more commonly demonstrated a spontaneous motogenic activity than those with the wild-type ras genotype. When tumour cells were grown in collagen gels, HGF/SF induced irregular branching extensions of cell aggregates formed by five out of eight adenocarcinoma cell lines, but significant lumen morphogenesis was distinctly absent. The presence of autocrine HGF/SF loop in these tumour cell lines did not influence their spontaneous or HGF/SF-induced mitogenic, motogenic or morphogenic activities. Overall, our data suggest that stimulation of cell motility, rather than proliferation or differentiation, is the predominant paracrine effect of HGF/SF on NSCLC cells in vitro.     

Kinematic navigation in total knee replacement--experience from the first 50 cases.

BACKGROUND/PURPOSE: Proper alignment of the prosthesis is critical in total knee replacement (TKR) to minimize long-term wear, risk of osteolysis, and loosening of the prosthesis. This study examined the accuracy of lower limb alignment obtained using a kinematic navigation system for TKR, and the extra time needed to adopt this system. METHODS: From August 2002 to April 2003, 71 patients with knee osteoarthritis underwent 79 primary TKR operations by the same surgical team. Fifty of these operations were performed with the aid of the CT-free kinematic navigation system, and the remaining 29 were performed with conventional manual methods. Results, including operation time, radiographic alignment of the prosthesis and complications, for the two groups were compared. RESULTS: Patients in the kinematic navigation group achieved better accuracy in the coronal plane than the conventional group in terms of postoperative mechanical axis (1.89 +/- 0.63 degrees vs. 3.38 +/- 1.07 degrees ). Less variation was noted in the navigation group (femur: SD 1.88 degrees vs. 7.12 degrees ; tibia: SD 1.54 degrees vs. 2.99 degrees ), although the difference in the mean values was not significant (p = 0.475 and 0.55, respectively). The operation time (from skin to skin) in the navigation group (100.6 +/- 4.3 minutes) was longer than that in the conventional group (92.7 +/- 5.1 minutes; p = 0.027). Two perioperative fractures occurred in the navigation group, both of which were attributed to patient factors as opposed to operation procedures. No major complications such as infection or pulmonary embolism occurred during this study. CONCLUSION: Use of a kinematic navigation system in TKR provides better accuracy than conventional manual methods. The technique is easy to use, has a short learning curve, and requires an additional operation time of less than 10 minutes. Precise alignment can be achieved with the aid of navigation in most cases.     

Interspeaker variation in habitual speaking rate: additional evidence.

PURPOSE: The purpose of the present study was to test the hypothesis that talkers previously classified by Y.-C. Tsao and G. Weismer (1997) as habitually fast versus habitually slow would show differences in the way they manipulated articulation rate across the rate continuum. METHOD: Thirty talkers previously classified by Tsao and Weismer (1997) as having habitually slow (n = 15; 7 males, 8 females) and habitually fast (n = 15; 8 males, 7 females) articulation rates produced a single sentence at 7 different rates, using a magnitude production paradigm. Hence, the participants were not randomly assigned to conditions. RESULTS: Quadratic regression functions relating measured to intended articulation rates were all statistically significant, and most important, there were significant differences between the slow and fast groups in the y intercepts of the functions, for both males and females. CONCLUSIONS: This study provides a constructive replication of Tsao and Weismer (1997), showing a difference between slow and fast talkers with a new set of speech materials and in a new task. The findings appear to be consistent with a biological basis for intertalker rate differences.     

Effects of Iron Supplementation on Testicular Function and Spermatogenesis of Iron-Deficient Rats

Iron deficiency is the most common micronutrient deficiency in the world. Previous studies have shown that iron deficiency increases oxidative stress and decreases antioxidant enzymes, and studies of male infertility indicated that oxidative stress may affect male reproductive functions. The aim of this study was to investigate the effects of iron supplementation on spermatogenesis and testicular functions in iron-deficient rats. Three-week-old male Sprague Dawley (SD) rats were randomly divided into two groups: an iron-adequate control (AI group, 35 ppm FeSO₄) and an iron-deficient group (ID group, <5 ppm FeSO₄). After three weeks, the iron-deficient group was divided into an original iron-deficient group and five iron-supplemented groups, the latter fed diets containing different doses of FeSO₄ (6, 12, 18, 24, and 35 ppm). After five weeks, blood and testis tissue were analyzed. We presented as median (interquartile range, IQR) for continuous measurements and compared their differences using the Kruskal–Wallis test followed by the Mann–Whitney U test among groups. The results showed that as compared with the AI group, the ID group had significantly lower serum testosterone and poorer spermatogenesis (The medians (QR) were 187.4 (185.6–190.8) of AI group vs. 87.5 (85.7–90.4) of ID group in serum testosterone, p < 0.05; 9.3 (8.8–10.6) of AI group vs. 4.9 (3.4–5.4) of ID group in mean testicular biopsy score (MTBS], p < 0.05); iron supplementation reversed the impairment of testis tissue. In the testosterone biosynthesis pathway, iron supplementation improved the lowered protein expressions of hydroxysteroid dehydrogenases caused by iron deficiency. Additionally, decreased activities of glutathione peroxidase and catalase, and increased cleaved-caspase 8 and caspase 3 expression, were found in the iron-deficient rats. The iron-supplemented rats that received > 12 ppm FeSO₄ exhibited improvements in antioxidant levels. In conclusion, iron supplementation can abrogate testis dysfunction due to iron deficiency through regulation of the testicular antioxidant capacity.     

Biosynthesis of the ansamycin antibiotic ansatrienin (mycotrienin) by Streptomyces collinus

The biosynthesis of ansatrienin (mycotrienin) has been studied in radioactive and stable isotope feeding experiments with Streptomyces collinus Tü 1892. The m-C7N unit of the ansa ring is efficiently and specifically derived from 3-amino-5-hydroxybenzoic acid; shikimic acid is not incorporated into this part of the molecule but does label the cyclohexanecarboyxlic acid moiety, providing all seven of its carbon atoms. Incorporation of methionine confirms origin of the methoxy group by transmethylation. The D-alanine moiety is derived directly from D-alanine rather than L-alanine. The terminal steps in the conversion of shikimic acid into cyclohexanecarboyxlic acid seem to be sequential reduction of 2,5-dihydrobenzoic acid and cyclohexene-1-carboxylic acid as evidenced by feeding experiments and the detection of a new ansatrienin containing a 1-cyclohexene instead of the cyclohexane moiety.     

Right- and Left-Subclavian Vein Port-A-Cath Systems: Comparison of Complications

Background: Central venous access systems are frequently used for delivery of medications; however, few studies have compared surgical and postoperative complications of right versus left access via the subclavian vein (SCV). The aim of this study was to compare the surgical and postoperative complications associated with Port-A-Cath system insertion via the right and left SCV. Methods: The medical records of patients who received Port-A-Cath insertion via the SCV for parenteral chemotherapy between August 2004 and July 2008 were reviewed. The incidence of surgical and postoperative complications was compared between patients who received right- versus left-SCV Port-A-Cath insertion. Results: A total of 1,848 patients were included in the study. Right-SCV catheterization was attempted in 1,029 (55.7%) patients and was successful in 866 (84.2%). Left-SCV catheterization was attempted in 819 (44.3%) patients and was successful in 651 (79.5%). The mean length of postoperative follow-up was 417.3 ± 401.3 and 396.7 ± 379.9 days for the right- and left-SCV groups, respectively. The incidence of SCV puncture failure was significantly lower in the right-SCV group (12.3%) compared with the left-SCV group (16.8%, p = 0.006). The incidence of catheter knotting at the ipsilateral brachiocephalic vein was also significantly lower in the right-SCV group (0.0%) compared with the left-SCV group (0.5%, p = 0.038), as was the incidence of catheter occlusion (1.0% for right SCV vs. 3.5% for left SCV, p = 0.001). Conclusion: These findings suggest that the right-SCV approach is superior to the left-SCV approach for Port-A-Cath insertion.     

Biomechanical investigation of titanium elastic nail prebending for treating diaphyseal long bone fractures

This study numerically investigated the deformation of titanium elastic nails prebent at various degrees during implantation into the intramedullary canal of fractured bones and the mechanism by which this prebending influenced the stability of the fractured bone. Three degrees of prebending the implanted portions of the nails were used: equal to, two times, and three times the diameter of the intramedullary canal. Furthermore, a simulated diaphyseal fracture with a 5-mm gap was created in the middle shaft portion of the bone fixed with two elastic nails in a double C-type configuration. End caps were simulated using a constraint equation. To confirm that the simulation process is able to present the mechanical response of the nail inside the intramedullary, an experiment was conducted by using sawbone for validation. The results indicated that increasing the degrees of nail prebending facilitated straightening the nails against the inner aspect of canal after implantation, with increase in stability under torsion. Furthermore, reducing nail prebending caused a larger portion of the nails to move closer to the loading site and center of bone after implantation; the use of end caps prevented the nail tips from collapsing and increased axial stability. End cap use was critical for preventing the nail tips from collapsing and for increasing the stability of the nails prebent at a degree equal to the diameter of the canal with insufficient frictional force between the nail and canal. Therefore, titanium elastic nail prebending in a double C-type configuration with a degree three times the diameter of the canal represents a superior solution for treating transverse fractures without a gap, whereas that with a degree equal to the diameter of the intramedullary canal and combined with end cap use represents an advanced solution for treating comminuted fractures in a diaphyseal long bone fracture.