Cytogenetic studies of some species complexes of Anopheles in Thailand and Southeast Asia

Recent studies on cytogenetics, behavioral, geographical and distinct morphological characters on adult, pupal and larval stages have revealed that "balabacensis" is a species complex. Anopheles dirus the mainland species, is distributed widely in Thailand and is renowned for its role as primary vector of human malarial parasites. Further, evidence from cytogenetic and taxonomic studies suggests that "An. dirus" is a species complex comprising at least four distinct species provisionally designated: dirus A, B, C and D. These cryptic species are distinguishable only partially morphologically, but can be separated on the basis of metaphase chromosomes using the Giemsa and Hoechst 33258 staining techniques. Apparently, these siblings show distinct patterns of geographic distribution in Thailand and Peninsular Malaysia. The recognition of dirus as a complex of species in Thailand and Peninsular Malaysia requires a re-evaluation of the role that the individual members of this complex have in the transmission of malaria parasites in this region. Cytological analysis of gene rearrangements in ovarian polytene chromosomes has shown that An. maculatus is a sibling-species complex consisting of at least four species in Thailand provisionally designated: maculatus A, B, C and G. These siblings are sympatric in some populations. Furthermore, species B is so highly polymorphic for chromosome rearrangements that four geographic forms can be recognized. It is not known whether these four forms are subspecies or yet further species within the species B complex. These sibling-species must be differentiated in order to understand any differential capabilities in their transmission of human malaria parasites. Anopheles nivipes was elevated from synonymy under An. philippinensis to full species status by Reid, a decision recently confirmed by cross mating experiments. The Thailand Malaria Division does not differentiate these two species and only identifies An. philippinensis, yet, An. nivipes is by far the most common of the two species in Thailand. Furthermore, preliminary surveys of the ovarian polytene chromosomes of several widely separated populations of An. nivipes in Thailand have revealed at least two distinct chromosomal types of nivipes based on fixed inversions on the X chromosomes.     

In vitro studies of intragastric digestion

Following consumption of a meal, 99% of the large food particles are emptied only after intragastric fragmentation has reduced their diameter to less than 2 mm. Anin vitro model was constructed to evaluate some of the factors which may play a role in the process of intragastric digestion. Gastric mixing of food was simulated in a silicone rubber tube (ID 19 mm) placed in a peristaltic pump. Peristaltic waves progressed upwards along the tube at a frequency of 0, 1, or 3/min, reducing the internal diameter of the tube to 5 mm. Cooked chicken liver particles (2–2.8 mm in diameter) were placed in the tube with one of the following: (1) 150 mM NaCl, (2) 150 mM HCl with or without pepsin, or (3) phosphate buffer at pH 7, 5.4, or 2.6 + pepsin. After 30 min, the extent of particle reduction and of solubilization of proteins were determined and expressed as percent of the initial liver weight. The diameter of liver particles was reduced to a greater extent in NaCl than in pH 7 buffer or acid solutions with or without pepsin. In contrast, the amount of proteins solubilized was enhanced two- to threefold by acid pepsin solutions compared to NaCl or pH 7 phosphate. The presentin vitro studies suggest that changes in motor and/or secretory activity of the stomach significantly modify intragastric digestion.     

Versorgung der per- bis subtrochantären Femurfraktur durch Gammanagel und modulare Hüftprothese Differentialindikation und Ergebnisse

From January 1997 to August 1998 all stable and nonstable trochanteric femoral fractures (n = 72) were treated routinely by gamma nail using the correct operative technique. Patients showing additional osteoarthritis of the hip in radiographs hip replacement was performed by a cementless modular femoral hip prostheses from January 1996 to August 1998 (n = 28). Follow up period was 6 to 18 months. Operation time and blood loss were higher using the prostheses. However complications and lethality (< 5%) were not different during postoperative course. In each group three operative technical complications occurred. Using a modified Harris Hip Score (without range of motion, contractions) the score was decreased non significant comparing both groups first of all in unstable fractures until follow up. In each group one revision (loosening of prostheses, excessive shortening of femoral neck) was necessary. Using the correct operative technique, the gamma nail proved to be a save device with good outcome. Outcome using modular prostheses is comparable to gamma nail. Therefore the use of modular prostheses is justified in case of osteoarthrosis and in some cases of very unstable fracture.     

Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma.

PURPOSE: Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 microg/kg once daily for 5 days every 3 weeks, up to eight cycles. RESULTS: Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25- histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient. CONCLUSION: Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25- B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.     

Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer.

PURPOSE: To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study. PATIENTS AND METHODS: Three hundred sixty-eight patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life. RESULTS: The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P =.376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms. CONCLUSION: Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.     

Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial.

PURPOSE: This randomized, 2 x 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes' B2) and III (Dukes' C) colon cancer. PATIENTS AND METHODS: LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion. RESULTS: A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P =.74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P =.63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P =.18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P <.001). CONCLUSION: Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations.     

Skp2 protein expression in soft tissue sarcomas.

BACKGROUND: p45 S phase kinase-associated protein-2 (p45(skp2)), a member of the F-box family of proteins, is an important component of the Skp1-Cullin-F-box protein (SCF) ubiquitin-ligase complex (SCF(skp2)). The latter has been implicated in the ubiquitination and degradation of p27(kip1) (p27) and G(1)-S cell cycle progression. The expression and prognostic role of Skp2 in a large series of soft tissue sarcomas has not been previously investigated. METHODS: Clinicopathologic features and immunohistochemical expression of Skp2, p27, and Ki-67 proteins were studied in 182 cases of soft tissue sarcomas (American Joint Committee on Cancer stages II and III). Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. RESULTS: The male to female ratio was 1.2:1, and the median age at the diagnosis was 53 years. The tumors were predominantly located in the lower extremities (n = 163; 90%) and had a median size of 9 cm. High Skp2 expression (> or = 10% of the cells) was identified in 68 tumors (37%), and was correlated with high grade histology (P =.002) and Ki-67 proliferative index (r = 0.44; P <.0001), but not with p27 expression (r = -0.02; P =.80). By univariate analysis, high Skp2 expression was associated with decreased metastasis-free, disease-free, and overall survival. In a multivariate model, high Skp2 expression was an independent predictor for decreased local recurrence-free, disease-free, and overall survival. CONCLUSION: These results indicate that Skp2 expression is associated with cell proliferation and a worse prognosis in soft tissue sarcomas. The lack of an inverse correlation between Skp2 and p27 suggests that additional molecular events associated with either Skp2 expression or p27 proteolysis may be operating in these tumors.     

Improving quality of care using a diabetes registry and disease management services in an integrated delivery network.

Disease management for chronic conditions is a call for collaboration among all parties of the health care system. The Caritas Christi Health Care System established a unified American Diabetes Association (ADA) recognized outpatient diabetes self-management education program (DSME) in each of its six hospital communities and has established an Internet data portal with managed care organizations to improve preventive care for thousands of patients with diabetes. This article describes the stepwise process of building the successful Caritas Diabetes Care Program and the central role of the Caritas Diabetes Registry over a 5-year period.     

Anticoagulant Use in Patients with Chronic Renal Impairment

Patients with renal failure have an increased risk of both thrombotic and bleeding complications. A number of antithrombotic drugs undergo renal clearance. Therefore, estimation of renal function is necessary when prescribing these drugs to patients with renal dysfunction. Pharmacokinetic and clinical data in patients with chronic renal impairment are limited for several anticoagulants, and adequate administration information is often absent. Dose adjustment of anticoagulants may be indicated when the creatinine clearance falls below 30 mL/min. Unfractionated heparin, argatroban, and vitamin K antagonists generally do not require dose adjustment with renal dysfunction. However, smaller doses of warfarin may be required to achieve a particular target international normalized ratio. Close monitoring of anticoagulation is recommended when argatroban or high doses of unfractionated heparin are administered in patients with severe chronic renal impairment. Low-molecular weight heparins, danaparoid sodium, hirudins, and bivalirudin all undergo renal clearance. Lower doses and closer anticoagulation monitoring may be advisable when these agents are used in patients with chronic renal failure. We recommend that fondaparinux sodium and ximelagatran (not yet licensed) be avoided in the presence of severe renal impairment and be used with caution in patients with moderate renal dysfunction. While acknowledging the lack of pharmacokinetic data, this review provides specific recommendations for the use of anticoagulants in patients with chronic renal impairment.     

Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27.

PURPOSE: Experience with sentinel node biopsy (SNB) after neoadjuvant chemotherapy is limited. We examined the feasibility and accuracy of this procedure within a randomized trial in patients treated with neoadjuvant chemotherapy. PATIENTS AND METHODS: During the conduct of National Surgical Adjuvant Breast and Bowel Project trial B-27, several participating surgeons attempted SNB before the required axillary dissection in 428 patients. All underwent lymphatic mapping and an attempt to identify and remove a sentinel node. Lymphatic mapping was performed with radioactive colloid (14.7%), with lymphazurin blue dye alone (29.9%), or with both (54.7%). RESULTS: Success rate for the identification and removal of a sentinel node was 84.8%. Success rate increased significantly with the use of radioisotope (87.6% to 88.9%) versus with the use of lymphazurin alone (78.1%, P = .03). There were no significant differences in success rate according to clinical tumor size, clinical nodal status, age, or calendar year of random assignment. Of 343 patients who had SNB and axillary dissection, the sentinel nodes were positive in 125 patients and were the only positive nodes in 70 patients (56.0%). Of the 218 patients with negative sentinel nodes, nonsentinel nodes were positive in 15 (false-negative rate, 10.7%; 15 of 140 patients). There were no significant differences in false-negative rate according to clinical patient and tumor characteristics, method of lymphatic mapping, or breast tumor response to chemotherapy. CONCLUSION: These results are comparable to those obtained from multicenter studies evaluating SNB before systemic therapy and suggest that the sentinel node concept is applicable following neoadjuvant chemotherapy.