Mortality studies of machining fluid exposure in the automobile industry. IV: A case-control study of lung cancer

The taxanes represent a new class of clinical chemotherapeutic agents. A series of in vitro studies were independently of each other initiated in two different institutes (Amsterdam and Madison) to test the hypothesis that hyperthermia might enhance the cytotoxicity of taxanes. Clonogenic capacity experiments (Amsterdam) included the exposure of R1- and SW 1573-cells to 1, 4, or 24 h of paclitaxel with heat 43 degrees C x 60 min in the last hour of drug treatment or at 24, 48 as well as 72 h post drug treatment. Survival assay experiments (Madison) included the exposure of L-929-cells to paclitaxel and docetaxel for 24 h with heat 41.8 degrees C x 60 min the first or last hour of drug treatment as well as 24 and 48 h post treatment. No thermal enhancement of cytotoxicity for the taxanes was observed in these human and murine cell lines, with congruent data in both institutes. In addition, high performance liquid chromatography studies at 41.8 degrees C and 43 degrees C demonstrated paclitaxel and docetaxel were heat stable.     

Aneurysm of superficial temporal artery in angiolymphoid hyperplasia lesions

Parent or self-reported history of fractures in a group of patients aged from 0.3 to 33.6 years on dietary treatment for phenylketonuria was studied by means of a questionnaire. Twenty-one of 85 patients had a history of fracture compared with 18/98 sibling controls. There was no significant difference in the lifetime risk of fracture between patients and controls (chi 2 = 1.43, df = 1, p = 0.23), but a significantly higher risk of fracture was reported over the age of 8 y (chi 2 = 5.11, df = 1, p = 0.024), with a relative risk of 2.6 (95% confidence interval 1.1.6.1). We suggest this may be related either to deterioration in dietary control in this age group or to a cumulative disease-related or diet-related reduction in bone mass.     

Influence of tempering on the feeding value of rolled corn in finishing diets for feedlot cattle

Crossbred yearling steers (n = 125; 372 kg) were used in a 109-d finishing trial. Steers were fed an 88% concentrate diet containing 65% corn (DM basis) as 1) dry rolled corn (DRC); 2) tempered rolled corn (TRC), 43 mg surfactant (SarTemp)/kg corn; 3) TRC, 172 mg surfactant/kg corn; 4) TRC, 430 mg surfactant/kg corn; and 5) steam-flaked corn (SFC). Corn moisture was greater (3.5%, P < .01) for TRC than for DRC but less (10%, P < .05) than for SFC. Starch enzymatic reactivity was less for TRC than for either DRC (18%, P < .05) or SFC (42%, P < .01). Tempering increased the integrity of rolled corn and reduced the amount of particles less than 2 mm in diameter by 54% (P < .01). Steam flaking corn increased (P < .01) proportion (78%) of the grain having a particle size distribution of greater than 8 mm, as compared with TRC (25%) and DRC (3%). Compared with DRC, tempering enhanced (P < .10) ADG (9%), feed efficiency (5%), and dietary NE (3%). Daily weight gain was similar (P > .10) for TRC and SFC. Feed efficiency (P < .10) and dietary NE (P < .01) were greater (6%) for SFC than for TRC. There were no differences (P > .10) between DRC and TRC in ruminal and total tract digestion of OM, N, and starch, and in ruminal microbial efficiency. Ruminal digestion of OM decreased (linear effect, P < .05) and ruminal microbial efficiency increased (linear effect, P < .05) with increasing surfactant concentration. Ruminal digestion of OM and starch, and flow of nonammonia N to the small intestine were greater (31, 56, and 14%, respectively, P < .01) for SFC than for TRC. Postruminal and total tract digestion of OM, N, and starch, and dietary DE were greater (P < .01) for SFC than for TRC. We concluded that tempering corn will enhance animal performance. Increasing the concentration of surfactant used in tempering may enhance ruminal microbial efficiency and lean tissue growth.     

Angiotensin II AT1 receptor/signaling mechanisms in the biphasic effect of the peptide on proximal tubular Na+,K+-ATPase

The present study was designed to determine the cellular signaling mechanisms responsible for mediating the effects of angiotensin II on proximal tubular Na+,K+-ATPase activity. Angiotensin II produced a biphasic effect on Na+,K+-ATPase activity: stimulation at 10(-13) - 10(-10) M followed by inhibition at 10(-7) - 10(-5) M of angiotensin II. The stimulatory and inhibitory effects of angiotensin II were antagonized by losartan (1nM) suggesting the involvement of AT1 receptor. Angiotensin II produced inhibition of forskolin-stimulated cAMP accumulation at 10(-13) - 10(-10) M followed by a stimulation in basal cAMP levels at 10(-7) - 10(-5) M. Pretreatment of proximal tubules with losartan (1nM) antagonized both the stimulatory and inhibitory effects of angiotensin II on cAMP accumulation. Pretreatment of the proximal tubules with pertussis toxin (PTx) abolished the stimulation of Na+,K+-ATPase activity but did not affect the inhibition of Na+,K+-ATPase activity produced by angiotensin II. Pretreatment of the tubules with cholera toxin did not alter the biphasic effect of angiotensin II on Na+,K+-ATPase activity. Mepacrine (10microM), a phospholipase A2 (PLA2) inhibitor, reduced only the inhibitory effect of angiotensin II on Na+,K+-ATPase activity. These results suggest that the activation of AT1 angiotensin II receptors stimulates Na+,K+-ATPase activity via a PTx-sensitive G protein-linked inhibition of adenylyl cyclase pathway, whereas the inhibition of Na+,K+-ATPase activity following AT1 receptor activation involves multiple signaling pathways which may include stimulation of adenylyl cyclase and PLA2.     

An improved synthesis of oligodeoxynucleotide N3'-->P5' phosphoramidates and their chimera using hindered phosphoramidite monomers and a novel handle for reverse phase purification

Oligodeoxynucleotide N3'-->P5' phosphoramidates are promising candidates for antisense therapeutics, as well as for diagnostic applications. We recently reported a new method for the synthesis of these oligonucleotide analogs which makes use of a phosphoramidite amine-exchange reaction in the key coupling step. We report herein an improved set of monomers that utilize a more reactive, hindered phosphoramidite to produce optimal yields in a single coupling step followed by oxidation, thereby eliminating the need for the previously reported couple-oxidize-couple-oxidize approach. On the 10 micromol scale, the synthesis is performed using only 3.6 equivalents (equiv.) of monomer. An improved oxidation reagent consisting of hydrogen peroxide, water, pyridine and THF is also introduced. Reported here for the first time is the use of a reverse-phase purification methodology employing a ribonucleotide purification handle that is removed under non-acidic conditions, in contrast to the conventional dimethoxytrityl group. The synthesis and purification of uniformly modified N3'-->P5' phosphoramidate oligodeoxy-nucleotides, as well as their chimera containing phosphodiester and/or phosphorothioate linkages at predefined positions, using these new methodologies are included herein. The results of31P NMR studies that led to this improved amine-exchange methodology are also described.     

Continuous positive airway pressure requirement during the first month of treatment in patients with severe obstructive sleep apnea

OBJECTIVES: (1) To compare the continuous positive airway pressure (CPAP) requirement at the time of diagnosis (T0), after 2 weeks (T2), and after 4 weeks (T4) of CPAP treatment, in patients with severe obstructive sleep apnea (OSA); and (2) to assess whether any alteration in CPAP requirement over the first 4 weeks of CPAP treatment would influence daytime alertness, subjective sleepiness, or mood. DESIGN: A prospective, controlled, single-blind crossover study. SETTING: University teaching hospital. PATIENTS: Ten patients with newly diagnosed and previously untreated severe OSA (aged 52+/-9 years, apnea hypopnea index [AHI] of 99+/-31) and subsequently 10 control patients (aged 52+/-11 years, AHI 85+/-17). MEASUREMENTS: Overnight polysomnography with CPAP titration to determine the CPAP requirement, which was standardized for body position and sleep stage, on all three occasions (T0, T2, T4). Objective sleep quality, daytime alertness, subjective sleepiness (Epworth Sleepiness Scale), and mood (Hospital Anxiety and Depression Scale). RESULTS: CPAP requirement decreased from T0 to T2 (median difference, 1.5 cm H2O, 95% confidence interval [CI], 1.1 to 2.7 cm H2O, p=0.0004) and did not differ between T2 and T4. Use of the lower CPAP pressure during T2 to T4 was associated with a decrease in Epworth scale (mean difference, 2.6, 95% CI, 1.2 to 4; p=0.01) and anxiety (median change, 2; 95% CI, 0.5 to 2.9, p=0.03) scores, as compared with the first 2 weeks. Daytime alertness did not differ between T0 to T2 and T2 to T4. CONCLUSION: CPAP requirement falls within 2 weeks of starting CPAP treatment. A change to the lower required CPAP was not associated with any deterioration in daytime alertness but was associated with small subjective improvements in sleepiness and mood.