Hypoxia, temperature, and pH/CO2 effects on respiratory discharge from a turtle brain stem preparation

An in vitro brain stem preparation from adult turtles (Chrysemys picta) was used to examine the effects of anoxia and increased temperature and pH/CO2 on respiration-related motor output. At pH approximately 7.45, hypoglossal (XII) nerve roots produced patterns of rhythmic bursts (peaks) of discharge (O.74 +/- 0.07 peaks/min 10.0 +/- 0.6 s duration) that were quantitatively similar to literature reports of respiratory activity in conscious, vagotomized turtles. Respiratory discharge was stable for 6 h at 22 degrees C; at 32 degrees C, peak amplitude and frequency progressively and reversibly decreased with time. Two hours of hypoxia had no effect on respiratory discharge. Acutely increasing bath temperature from 22 to 32 degrees C decreased episode and peak duration and increased peak frequency. Changes in pH/CO2 increased peak frequency from zero at pH 8.00-8.10 to maxima of 0.81 +/- 0.01 and 1.44 +/- 0.02 peaks/min at 22 degrees C (pH 7.32) and 32 degrees C (pH 7.46), respectively; pH/CO2 sensitivity was similar at both temperatures. We conclude that 1) insensitivity to hypoxia indicates that rhythmic discharge does not reflect gasping behavior, 2) increased temperature alters respiratory discharge, and 3) central pH/CO2 sensitivity is unaffected by temperature in this preparation (i.e., Q10 approximately 1.0).     

O6-methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma

Resistance of tumour cells to methylating and monochloroethylating agents in vitro and in vivo has been linked to levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In a clinical trial of temozolomide in advanced malignant melanoma, the relationship between pretreatment MGMT levels in biopsies of cutaneous tumours and involved lymph nodes and clinical response to the drug has been studied. Among 50 evaluable patients, there were three complete responses (CR), four partial responses (PR), six with stable disease (SD) and 37 with progressive disease (PD), with an overall response rate of 14%. In 33 patients in whom MGMT level and clinical response could be evaluated, the tumour MGMT levels (fmol mg(-1) protein) were: CR, 158 +/- 119; PR, 607 +/- 481; NC, 171 +/- 101; PD, 185 +/- 42.3. Thus, measurements of pretreatment levels of MGMT in melanoma did not predict for response to temozolomide.     

Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma

BACKGROUND: This study was designed to evaluate the efficacy and toxicity of the combination of 5-fluorouracil, interferon-alpha, and interleukin-2 for patients with metastatic renal cell carcinoma. METHODS: Previously untreated patients with a Zubrod performance status of < or =2; adequate cardiac, pulmonary, and renal function; and absence of brain metastases were eligible. One course of therapy was 28 days. 5-fluorouracil was administered at a dose of 600 mg/m2/day as a continuous infusions on Days 1-5. Interleukin-2 also was administered as a continuous infusion on Days 1-5 at a dose of 2 million Roche U/m2/day. Interferon-alpha was given as a daily subcutaneous injection of 4 million U/m2/day. RESULTS: Fifty-five patients were enrolled in the trial and 52 were evaluable for response. All patients experienced fever and flu-like symptoms. Grade 3 or 4 nonhematologic toxic effects included hypertension (48%), dermatitis (12%), stomatitis (11%), and altered mental status (9%). There was one toxic death. Four complete responses and 12 partial responses were observed for a total response rate of 31% (95% confidence interval, 18-46%). The survival of responding patients was significantly better than that of nonresponding patients. The improvement in survival was even more significant when comparing patients with at least stable disease with those who progressed through treatment. CONCLUSIONS: The three-drug combination described in this study demonstrates activity. However, it appears to be more toxic than other regimens with similar response rates and cannot be recommended for standard practice. Changing the interleukin-2 route to subcutaneous administration may permit more continuous administration with less toxic effects.     

Strength recovery in fractured sheep tibia treated with a plate or an internal fixator: an experimental study with a two-year follow-up

Lung adenocarcinoma is the most common cell type in females (smokers or non-smokers) and in non-smoking males. Its incidence has been increasing in younger cohorts of males and females until very recent years. Changes in classification and in pathological techniques account for some of this increase. In females and non-smoker males, the increase could be partly due to a detection bias in former studies. Nevertheless, successive cohorts over time seem more likely to develop adenocarcinoma and less likely to develop squamous cell carcinoma. These differences between birth cohorts suggest that the increasing incidence of adenocarcinoma is not only due to changes in pathological diagnosis. Geographical differences are also observed: in Europe, the squamous cell type still predominates and an increase in incidence of adenocarcinoma has only been reported in the Netherlands. In Asia, in the 1960s and 1970s, the proportion of adenocarcinoma was higher than in North America or Europe and seems to be increasing. To what extent these differences are due to differences. In establishing diagnosis remains unknown. Despite these biases in temporal and geographical trends detailed in this review, there has probably been a true increase in incidence of adenocarcinoma. An explanation for this should be sought in studies on detailed smoking history and passive smoking exposure, occupational exposure, diet and cooking, pollution and other environmental factors.     

alpha-Oligodeoxyribonucleotide N3'-->P5' phosphoramidates: synthesis and duplex formation

The synthesis and hybridization properties of novel nucleic acid analogs, alpha-anomeric oligodeoxyribonucleotide N3'-->P5' phosphoramidates, are described. The alpha-3'-aminonucleoside building blocks used for oligonucleotide synthesis were synthesized from 3'-azido-3'-deoxythymidine or 3'-azido-2',3'-dideoxyuridine via acid catalyzed anomerization or transglycosylation reactions. The base-protected alpha-5'-O-DMT-3'-aminonucleosides were assembled into dimers and oligonucleotides on a solid support using the oxidative phosphorylation method.1H NMR analysis of the alpha-N3'-->P5' phosphoramidate dimer structures indicates significant differences in the sugar puckering of these compounds relative to the beta-N3'-->P5' phosphoramidates and to the alpha-phosphodiester counterparts. Additionally, the ability of the alpha-oligonucleotide N3'-->P5' phosphoramidates to form duplexes was studied using thermal denaturation experiments. Thus the N3'-->P5' phosphoramidate decamer containing only alpha-thymidine residues did not bind to poly(A) and exhibited lower duplex thermal stability with poly(dA) than that for the corresponding beta-anomeric phosphoramidate counterpart. A mixed base decamer alpha-CTTCTTCCTT formed duplexes with the RNA and DNA complementary strands only in a parallel orientation. Melting temperatures of these complexes were significantly lower, by 34-47 or 15-25 degrees C, than for the duplexes formed by the isosequential beta-phosphoramidates in antiparallel and parallel orientations respectively. In contrast, the alpha-decaadenylic N3'-->P5' phosphoramidate formed duplexes with both RNA and DNA complementary strands with a stability similar to that of the corresponding beta-anomeric phosphoramidate. Moreover, the self-complementary oligonucleotide alpha-ATATATATAT did not form an alpha:alpha homoduplex. These results demonstrate the effects of 3'-aminonucleoside anomeric configuration on sugar puckering and consequently on stability of the duplexes.     

Specificity of the BAX polymerase chain reaction system for detection of the foodborne pathogen Listeria monocytogenes

PURPOSE: The purpose of this study was to evaluate the toxicity and efficacy of twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. METHODS AND MATERIALS: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and para-aortics at 4- to 6-h intervals, 5 days per week. The total external radiation doses were 24 to 48 Gy to the whole pelvis, 12 to 36 Gy parametrial boost, and 48 Gy to the para-aortics with an additional boost to a total dose of 54 to 58 Gy to the known metastatic para-aortic site. One or two intracavitary applications were performed to deliver a total minimum dose of 85 Gy to point A. Cisplatin (75 mg/m2, days 1 and 22) and 5-FU (1000 mg/m2/24 h x 4 days; days 1 and 22) were given for two or three cycles. RESULTS: Twenty-nine patients with clinical Stages I to IV carcinoma of the cervix with biopsy-proven para-aortic lymph nodes were enrolled in this study. Hyperfractionated external radiotherapy was completed in 86% (25 of 29). Brachytherapy was given in two applications to 48% (14 of 29), 31% (9 of 29) had one intracavitary application, 14% (4 of 29) had no brachytherapy, one had three applications, and one had five HDR applications. Radiotherapy was completed per protocol in 69%. Three courses of chemotherapy were given to 24% (7 of 29), 72% (21 of 29) received two courses, and one patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Radiotherapy toxicity was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. One Grade 5 toxicity occurred and the patient died from a myocardial infarction from chemotherapy and radiotherapy colitis during her course of therapy. The median follow-up time was 18.9 months. The overall survival estimates were 59% at 1 year and 47% at 2 years. The probability of local-regional failure was 38% at 1 year and 49% at 2 years. The probability of disease failure at any site was 45% at 1 year and 59% at 2 years. CONCLUSION: The results suggest that twice-daily external irradiation to the pelvis and para-aortics with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (31%, 9 of 29) of Grade 4 nonhematologic toxicity. One patient died from complications of therapy. Radiotherapy was completed per protocol in 69%. The survival estimates appear no better than standard fractionation radiotherapy without chemotherapy. Additional follow-up is necessary for long-term survival estimates.     

Impact of erythromycin on respiratory colonization of Ureaplasma urealyticum and the development of chronic lung disease in extremely low birth weight infants

BACKGROUND: Chronic lung disease (CLD) is a significant cause of neonatal morbidity and mortality despite advances in neonatal care. Ureaplasma urealyticum colonization of the lower respiratory tract has been associated with CLD, particularly in extremely low birth weight infants. Despite numerous studies demonstrating the pathogenicity of this organism, treatment remains controversial. This study examines neonates colonized with U. urealyticum in the lower respiratory tract and treated with erythromycin, as compared with noncolonized neonates. METHODS: A prospective cohort study of 124 neonates weighing <1000 g at birth, requiring endotracheal intubation and ventilation. Endotracheal aspirates were cultured for U. urealyticum and conventional bacteria twice weekly for the duration of endotracheal intubation. Infants colonized with U. urealyticum were treated with intravenous erythromycin. Maximal ventilatory requirements, CLD at Day 28 and 36 weeks postconception, duration of ventilation, oxygen dependency and hospital stay were documented. RESULTS: Twenty-two infants (18%) were identified as being U. urealyticum colonized in endotracheal aspirates. Colonization was significantly associated with younger maternal age, prolonged rupture of membranes, premature labor and vaginal delivery. Of colonized neonates 14% were delivered by cesarean section, with intact membranes. As compared with noncolonized infants, there were no statistically significant differences in chronic lung disease, duration of oxygen therapy or time to discharge. CONCLUSIONS: Seven published cohort studies of similar high risk populations where U. urealyticum-colonized infants did not receive erythromycin therapy, show a consistent association with CLD (pooled relative risk + 5.21; 95% confidence interval, 2.93 to 9.64). This association was not demonstrated in the current study and adds further weight to the need for a randomized controlled trial to be performed to evaluate this treatment regimen.