Paclitaxel plus high-dose cyclophosphamide with G-CSF support in patients with relapsed and refractory aggressive non-Hodgkin's lymphoma

Based on the single-agent activity of both paclitaxel and cyclophosphamide in the treatment of non-Hodgkin's lymphoma (NHL), we conducted a phase II study to evaluate the efficacy of the combination of the two drugs in patients with refractory and relapsed aggressive NHL. All patients received 900 mg/m2 bolus of cyclophosphamide intravenously daily for 3 consecutive days with a concurrent infusion of 150 mg/m2 of paclitaxel over 72 h (50 mg/m2/d). 24 h after the completion of chemotherapy, patients received subcutaneous injections of 5 microg/kg of granulocyte-colony stimulating factor (G-CSF) daily until white cell count recovery. Treatment was repeated every 3 weeks. Patients who had at least a partial response (PR) after two courses continued to receive a maximum of four courses. Patients with responding disease were allowed to undergo high-dose chemotherapy followed by stem-cell/bone marrow transplantation if they were eligible. Of the 77 patients who were eligible for the study, 74 (96%) were evaluable for toxicity and treatment response. The overall response rate was 45% (95% CI 33-57%). Patients who received treatment after their disease relapsed from a complete response (CR) had an 81% response rate (38% CRs), whereas those with primary refractory disease had a 22% response rate. Toxicities of > grade 2 included alopecia (100%) and stomatitis (25%). Neutropenic fever of grade > 2 occurred after 18% of the courses, and platelet count of < or = 20 x 10(9)/l developed after 20% of the courses. Thus, the combination of paclitaxel plus high-dose cyclophosphamide is an effective new regimen in the treatment of refractory and relapsed NHL.     

Effects of a quick-release form of bromocriptine (Ergoset) on fasting and postprandial plasma glucose, insulin, lipid, and lipoprotein concentrations in obese nondiabetic hyperinsulinemic women

OBJECTIVE: To assess the effect on various aspects of carbohydrate and lipid metabolism of administering a quick-release formulation of bromocriptine (Ergoset) to obese, nondiabetic, hyperinsulinemic women. RESEARCH DESIGN AND METHODS: Hourly concentrations of prolactin, glucose, insulin, free fatty acid (FFA), and triglyceride were measured for 24 h before and after approximately 8 weeks of treatment with Ergoset. In addition, fasting lipid and lipoprotein concentrations and the steady-state plasma glucose (SSPG) concentration in response to a continuous infusion of somatostatin, insulin, and glucose were determined before and after Ergoset administration. RESULTS: Circulating prolactin concentrations were dramatically decreased (P < 0.001) following treatment, associated with a significant fall (P < 0.05) in 24-h-long plasma glucose, FFA, and triglyceride concentrations. Neither circulating plasma insulin concentrations nor the ability of insulin to mediate glucose disposal changed with treatment. Finally, fasting total cholesterol fell (P < 0.05) and the ratio of total to HDL cholesterol decreased (P = 0.06) in association with Ergoset treatment. CONCLUSIONS: The fact that significant metabolic improvement was seen in the obese nondiabetic hyperinsulinemic women studied suggests that Ergoset could be of therapeutic benefit in clinical conditions of hyperglycemia and/or dyslipidemia.     

Transbuccal delivery of acyclovir: I. In vitro determination of routes of buccal transport

PURPOSE: To determine the major routes of buccal transport of acyclovir and to examine the effects of pH and permeation enhancer on drug permeation. METHODS: Permeation of acyclovir across porcine buccal mucosa was studied by using side-by-side through diffusion cells at 37 degrees C. The permeability of acyclovir was determined at pH range of 3.3 to 8.8. Permeability of different ionic species was calculated by fitting the permeation of data to a mathematical model. Acyclovir was quantified using HPLC. RESULTS: Higher steady state fluxes were observed at pH 3.3 and 8.8. The partition coefficient (1-octanol/buffer) and the solubility of acyclovir showed the same pH dependent profile as that of drug permeation. In the presence of sodium glycocholate (NaGC) (2-100 mM), the permeability of acyclovir across buccal mucosa was increased 2 to 9 times. This enhancement was independent of pH and reached a plateau above the critical micelle concentration of NaGC. The permeabilities of anionic, cationic, and zwitterionic species were 3.83 X 10-5, 4.33 X 10-5, and 6.24 x 10-6 cm/sec, respectively. CONCLUSIONS: The in vitro permeability of acyclovir across porcine buccal mucosa and the octanol-water partitioning of the drug were pH dependent. A model of the paracellular permeation of the anionic, cationic, and zwitterionic forms of acyclovir is consistent with these data. The paracellular route was the primary route of buccal transport of acyclovir, and the enhancement of transbuccal transport of acyclovir by sodium glycocholate (NaGC) appeared to operate via this paracellular route.     

A safe high-yield technique for cutting needle biopsy of the lung in patients with diffuse lung disease

The approach to the diagnosis and management of patients with diffuse infiltrative lung disease (DILD) is controversial. The results of transbronchial biopsy are often unsatisfactory. The role of open lung biopsy is highly variable. Percutaneous cutting needle biopsy (CNB) is not recommended because of its reported high morbidity/mortality relative to its low diagnostic yield. We report a technique for CNB with a high diagnostic yield and a low morbidity and no mortality in 228 patients with DILD over the past 23 years. METHODS: The salient features of the technique for CNB are as follows: the anesthetic needle does not enter the pleural space; a Franklin Silverman needle is inserted into the intercostal space posteriorly at outer one-third of chest wall; the biopsy is performed with the breath held at normal end expiration; the plane of pleural space is broken with sudden insertion of needle 8 to 15 cm into lung; and the pathway of the needle is maintained parallel to the lateral chest wall. RESULTS: A diagnosis was established in 129 of 145 biopsies (89%) performed by a trained operator (A.H.N.). There were 36 pneumothoraces (25%), four minimal hemoptyses (3%), and two chest tube placements (1%). There were no deaths (0%). CONCLUSION: With meticulous attention to technique and careful selection of patients, the procedure offers a relatively safe alternative to open lung or thoracoscopic lung biopsy in patients with DILD.     

Alfalfa yield response to inoculation with recombinant strains of Rhizobium meliloti with an extra copy of dctABD and/or modified nifA expression

The construction of rhizobial strains which increase plant biomass under controlled conditions has been previously reported. However, there is no evidence that these newly constructed strains increase legume yield under agricultural conditions. This work tested the hypothesis that carefully manipulating expression of additional copies of nifA and dctABD in strains of Rhizobium meliloti would increase alfalfa yield in the field. The rationale for this hypothesis is based on the positive regulatory role that nifA plays in the expression of the nif regulon and the fact that a supply of dicarboxylic acids from the plant is required as a carbon and energy source for nitrogen fixation by the Rhizobium bacteroids in the nodule. These recombinant strains, as well as the wild-type strains from which they were derived, are ideal tools to examine the effects of modifying or increasing the expression of these genes on alfalfa biomass. The experimental design comprised seven recombinant strains, two wild-type strains, and an uninoculated control. Each treatment was replicated eight times and was conducted at four field sites in Wisconsin. Recombinant strain RMBPC-2, which has an additional copy of both nifA and dctABD, increased alfalfa biomass by 12.9% compared with the yield with the wild-type strain RMBPC and 17.9% over that in the uninoculated control plot at the site where soil nitrogen and organic matter content was lowest. These increases were statistically significant at the 5% confidence interval for each of the three harvests made during the growing season. Strain RMBPC-2 did increase alfalfa biomass at the Hancock site; however, no other significant increases or decreases in alfalfa biomass were observed with the seven other recombinant strains at that site. At three sites where this experiment was conducted, either native rhizobial populations or soil nitrogen concentrations were high. At these sites, none of the recombinant strains affected yield. We conclude that RMBPC -2 can increase alfalfa yields under field conditions of nitrogen limitation, low endogenous rhizobial competitors, and sufficient moisture.     

Eucapnic voluntary hyperventilation as a bronchoprovocation technique: development of a standarized dosing schedule in asthmatics

A variety of dosing schedules have been reported for the hyperventilation method of broncho-provocation testing. To evaluate the effect of challenge technique on the bronchoconstrictive response, we had 16 subjects perform eucapnic voluntary hyperventilation (EVH) with dry, room temperature gas using four different dosing schedules. The hyperventilation challenge dosages included the following: (1) a target minute ventilation (VE) of 20 x FEV1 for 6 min; (2) a target VE of 15 x FEV1 for 12 min; (3) an interrupted challenge with a target VE of 30 x FEV1 for 2 min repeated 3 times; and (4) a target VE of 30 x FEV1 for 6 min. Challenges 2, 3, and 4 gave identical absolute ventilatory challenges (identical factor FEV1 x minutes) but at different VE dosages or time. Challenges 1 and 4 were of identical length, but different target VE. The mean postchallenge fall in FEV1 was 16.6 +/- 10.9%, 11.0 +/- 8.1%, 19.6 +/- 9.9%, and 26.7 +/- 11.3% for challenges 1, 2, 3, and 4, respectively. The response to an identical EVH challenge (FEV1 x 30 for 6 min) was reproducible when performed on separate days. We conclude that the challenge technique used for hyperventilation testing will have a significant impact on the bronchoconstrictive response and must be taken into account when interpreting study results. Tests may be quantitatively comparable over a narrow range of challenge time and VE. We recommend that a 6-min uninterrupted EVH challenge using dry, room temperature gas at a target VE of 30 x FEV1 be adopted as the "standard" challenge.     

Consequences of the photodynamic treatment of resting and activated peripheral T lymphocytes

Silencing of the cryptic mating-type loci HMR and HML requires the recognition of DNA sequence elements called silencers by the Sir1p, one of four proteins dedicated to the assembly of silenced chromatin in Saccharomyces cerevisiae. The Sir1p is thought to recognize silencers indirectly through interactions with proteins that bind the silencer DNA directly, such as the origin recognition complex (ORC). Eight recessive alleles of SIR1 were discovered that encode mutant Sir1 proteins specifically defective in their ability to recognize the HMR-E silencer. The eight missense mutations all map within a 17-amino-acid segment of Sir1p, and this segment was also required for Sir1p's interaction with Orc1p. The mutant Sir1 proteins could function in silencing if tethered to a silencer directly through a heterologous DNA-binding domain. Thus the amino acids identified are required for Sir1 protein's recognition of the HMR-E silencer and interaction with Orc1p, but not for its ability to function in silencing per se. The approach used to find these mutations may be applicable to defining interaction surfaces on proteins involved in other processes that require the assembly of macromolecular complexes.     

Ultrafast electron diffraction and direct observation of transient structures in a chemical reaction

Ultrafast electron diffraction is a unique method for the studies of structural changes of complex molecular systems. In this contribution, we report direct ultrafast electron diffraction study of the evolution of short-lived intermediates in the course of a chemical change. Specifically, we observe the transient intermediate in the elimination reaction of 1,2-diiodotetrafluoroethane (C2F4I2) to produce the corresponding ethylene derivative by the breakage of two carbon-iodine, C---I, bonds. The evolution of the ground-state intermediate (C2F4I radical) is directly revealed in the population change of a single chemical bond, namely the second C---I bond. The elimination of two iodine atoms was shown to be nonconcerted, with reaction time of the second C---I bond breakage being 17 +/- 2 ps. The structure of the short-lived C2F4I radical is more favorable to the classical radical structure than to the bridged radical structure. This leap in our ability to record structural changes on the ps and shorter time scales bodes well for many future applications in complex molecular systems.