Project Sandman: A Quasi-Experimental Evaluation of a Group-Based Brief Sleep Intervention in Air Force Technical Training.

OBJECTIVES: Approximately 70% of the military personnel experience chronic sleep insufficiency, which negatively impacts military readiness and health. Military sleep health does not appear to be improving despite targeted programs to optimize sleep. The present quasi-experimental study aims to evaluate a single-session sleep intervention in United States Air Force (USAF) Technical Training. METHOD: A group-based Brief Sleep Intervention (BSI) was developed for the target population. Participants included 321 technical school students (Mean age = 21; 82% male; 67% White) who were assigned to the BSI (n = 203) or a control group (n = 118). Propensity-score-weighted multivariable logistic regression was employed to compare outcomes. RESULTS: At the 2-week follow-up, students in the BSI were significantly more likely to report sleeping 6 or more hours on weekdays (OR = 1.49, p < .001) and "Good/Very Good" sleep quality (OR = 1.50, p = .032) than those in the control group. In addition, 69.2% of the students in BSI reported having engaged in the self-selected "Action Step" chosen during the intervention. CONCLUSIONS: To our knowledge, this is the first study to test a preventative sleep intervention in USAF Technical Training. Results suggest that a single-session group intervention can promote behavioral changes and improve sleep health.

Psychological, social and everyday visual impact of diabetic macular oedema and diabetic retinopathy: a systematic review.

AIMS: To synthesize the evidence on the impact of diabetic retinopathy and diabetic macular oedema from the patient perspective. METHODS: A systematic literature review was conducted using MEDLINE Complete, PsycINFO, EMBASE and AMED. We included articles investigating the impact of the condition on quality of life, symptoms, visual functioning, activities of daily living, well-being, social functioning, and financial status. The studies evaluated were observational, including cross-sectional, prospective cohort and retrospective cohort designs. Outcome data were extracted and synthesized. RESULTS: Searches yielded 5114 publications. After screening, 85 studies were included, measuring the following outcomes: visual functioning (n=46); quality of life (n=22); well-being (n=16); functional status (n=5); work (n=4); and visual task performance (n=2). Diabetic retinopathy has a considerable impact on visual functioning and this is greater in people with greater disease severity. Diabetic retinopathy significantly limits activities including working, driving, walking and reading, and has the potential to have a negative impact on psychological well-being. CONCLUSIONS: Diabetic retinopathy is associated with poor self-reported visual functioning, well-being, and health-related quality of life. Ability to perform basic everyday tasks appears to diminish with disease severity. Some studies suggest impaired mobility and problems with work, but there are gaps in this evidence.

Plasma ropivacaine concentrations during bilateral transversus abdominis plane infusions.

BACKGROUND: The transversus abdominis plane (TAP) block is a regional anaesthetic technique that blocks abdominal wall somatic afferent nerves. We conducted a prospective observational study to evaluate the venous plasma concentrations of ropivacaine during a continuous TAP infusion. METHODS: Twenty patients who were planned to undergo intra-abdominal cavity surgery requiring a mid-line laparotomy incision were enrolled. Patients were excluded if they had a history of chronic pain, opioid tolerance, renal or hepatic impairment, or contraindication to study medications. Subjects received a standardized general anaesthetic, and at the completion of surgery, ultrasound-guided subcostal or posterior TAP blocks and catheters. A TAP infusion of 2 mg ml(-1) ropivacaine was administered for 72 h after operation. Data collection during the 72 h included morphine requirements, pain scores, and plasma ropivacaine levels. RESULTS: TAP blocks and catheters were successfully inserted in all recruited subjects. The fourth subject experienced neurological symptoms attributed to local anaesthetic toxicity, but did not have high plasma ropivacaine concentrations. However, the protocol was amended for the subsequent 16 subjects, to a weight-based dosing regimen. The range of total plasma ropivacaine concentrations was 0.98-3.41 mg litre(-1) for posterior infusions and 0.96-3.48 mg litre(-1) for subcostal infusions. Four subjects had total ropivacaine levels >3.4 mg litre(-1). The range of unbound plasma ropivacaine concentrations was 0.022-0.135 mg litre(-1) for posterior infusions and 0.031-0.120 mg litre(-1) for subcostal infusions. CONCLUSION: Given the potential for high plasma concentrations from a bilateral TAP infusion technique, attention should be paid to individualized dosing strategies.

Spin density projection-assisted R2 magnetic resonance imaging of the liver in the management of body iron stores in patients receiving multiple red blood cell transfusions: an audit and retrospective study in South Australia.

AIM: To assess the impact of non-invasive monitoring of liver iron concentration (LIC) on management of body iron stores in patients receiving multiple blood transfusions. METHOD: A retrospective audit was conducted on clinical data from 40 consecutive subjects with haemolytic anaemias or ineffective haematopoiesis who had been monitored non-invasively for LIC over a period of at least 1 year. LIC was measured with spin density projection-assisted proton transverse relaxation rate-magnetic resonance imaging. RESULTS: Nineteen clinical decisions were explicitly documented in the case notes as being based on LIC results. Decisions comprised initiation of chelation therapy, increasing chelator dose, decreasing chelator dose and change of mode of delivery of deferioxamine from subcutaneous to intravenous. The geometrical mean LIC for the cohort dropped significantly (P= 0.008) from 6.8 mg Fe/g dry tissue at initial measurement to 4.8 mg Fe/g dry tissue at final measurement. The proportion of subjects with LIC in the range associated with greatly increased risk of cardiac disease and death (>15 mg Fe/g dry tissue) dropped significantly (P= 0.01) from 14 of 40 subjects at initial measurement to 5 of 40 subjects at final measurement. No significant changes in the geometrical mean of serum ferritin or the proportion of subjects with serum ferritin above 2500 or 1500 µg/L were observed. CONCLUSIONS: The data are consistent with previous observations that introduction of non-invasive monitoring of LIC can contribute to a decreased body iron burden through improved clinical decision making and improved feedback to patients and hence improved adherence to chelation therapy.

Adsorption of polyelectrolyte/surfactant mixtures at the air-water interface: modified poly(ethyleneimine) and sodium dodecyl sulfate.

The adsorption of surfactant/polyelectrolyte mixtures of sodium dodecyl sulfate (SDS) and different modified poly(ethyleneimine) (PEI) polyelectrolytes at the air-water interface has been studied using neutron reflectivity and surface tension. Modification of the PEI by the addition of short ethylene oxide (EO) or propylene oxide (PO) groups is shown to have an impact upon the surface adsorption behavior. This is due to a modification of the polymer/surfactant interaction, an increase in the intrinsic surface activity of the modified polyelectrolyte, and changes in the relative importance of surface and solution complex formation. For the polyelectrolyte PEI, there is a marked change in the surface adsorption behavior between the addition of a single EO group and that of the (EO)3 group. The addition of a single EO or PO group to the PEI results in an SDS concentration and solution pH adsorption dependence that is broadly similar in behavior to that of the unmodified PEI/SDS mixture. That is, there is strong surface complexation and adsorption down to low SDS concentrations, and there is evidence of a strong interaction at high pH in addition to the strong electrostatic attraction at low pH. The addition of a larger ethylene oxide group, triethylene oxide (EO)3, results in a surface adsorption behavior that more closely resembles that of a neutral polymer/ionic surfactant mixture, similar to that observed for PEI with a larger ethylene oxide group, notably PEI-(EO)7. In that case, the adsorption of the polymer/surfactant complex is much less pronounced. The adsorption arises predominantly from competition between the polymer and surfactant and indicates a decrease in the polymer/surfactant interaction with increasing pH. That is, increasing the size of the ethylene oxide group induces a transition from a strong surface polymer/surfactant interaction to a weak polymer/surfactant interaction.

The plasma levels of the endocannabinoid, anandamide, increase with the induction of labour.

OBJECTIVE: Plasma anandamide (AEA) levels have previously been shown to be elevated in labour and defective cannabinoid receptor type 1 signalling in mice has been shown to be associated with elevation of corticotrophin-releasing hormone and spontaneous onset of preterm labour. We measured plasma AEA levels in women undergoing induction of labour to define the changes during the transition from the nonlabouring to labouring state. DESIGN: A longitudinal observational study. SETTING: A large UK teaching hospital. POPULATION: Term pregnant women undergoing induction of labour. METHODS: Blood was collected from women before induction of labour and again when they were in active labour. Plasma AEA was extracted and measured using ultraperformance liquid chromatography-tandem mass spectrometry. MAIN OUTCOME MEASURES: The primary outcome variable was change in plasma AEA levels from the nonlabouring to the labouring state. The secondary outcome was induction-to-delivery interval. RESULTS: There was a 1.5-fold increase in mean plasma AEA levels from 1.20 +/- 0.57 nm in the nonlabouring state to 1.82 +/- 0.87 nm in the labouring state (P < 0.0001). Induction-to-delivery interval was predicted by both Bishop's score (P < 0.0001) and percentage change in plasma AEA levels (P < 0.0001). There was a negative correlation between the percentage change in plasma AEA level and the induction-to-delivery interval (r = - 0.28; P = 0.0481). This means that the greater the rise in the plasma AEA levels the shorter the duration of labour. CONCLUSIONS: Plasma AEA levels increase with active labour and the negative correlations between percentage change in plasma AEA levels and induction-to-delivery interval suggest that AEA is likely to be involved in the physiological mechanisms of labour. Whether this increase is essential for myometrial contraction is unclear and needs further investigation.

Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial.

BACKGROUND: The ORACLE I trial compared the use of erythromycin and/or amoxicillin-clavulanate (co-amoxiclav) with that of placebo for women with preterm rupture of the membranes without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study--the ORACLE Children Study I--was to determine the long-term effects on children of these interventions. METHODS: We assessed children at age 7 years born to the 4148 women who had completed the ORACLE I trial and who were eligible for follow-up with a structured parental questionnaire to assess the child's health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England. FINDINGS: Outcome was determined for 3298 (75%) eligible children. There was no difference in the proportion of children with any functional impairment after prescription of erythromycin, with or without co-amoxiclav, compared with those born to mothers who received no erythromycin (594 [38.3%] of 1551 children vs 655 [40.4%] of 1620; odds ratio 0.91, 95% CI 0.79-1.05) or after prescription of co-amoxiclav, with or without erythromycin, compared with those born to mothers who received no co-amoxiclav (645 [40.6%] of 1587 vs 604 [38.1%] of 1584; 1.11, 0.96-1.28). Neither antibiotic had a significant effect on the overall level of behavioural difficulties experienced, on specific medical conditions, or on the proportions of children achieving each level in reading, writing, or mathematics at key stage one. INTERPRETATION: The prescription of antibiotics for women with preterm rupture of the membranes seems to have little effect on the health of children at 7 years of age. FUNDING: UK Medical Research Council.

Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial.

BACKGROUND: The ORACLE II trial compared the use of erythromycin and/or amoxicillin-clavulanate (co-amoxiclav) with that of placebo for women in spontaneous preterm labour and intact membranes, without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study--the ORACLE Children Study II--was to determine the long-term effects on children after exposure to antibiotics in this clinical situation. METHODS: We assessed children at age 7 years born to the 4221 women who had completed the ORACLE II study and who were eligible for follow-up with a structured parental questionnaire to assess the child's health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England. FINDINGS: Outcome was determined for 3196 (71%) eligible children. Overall, a greater proportion of children whose mothers had been prescribed erythromycin, with or without co-amoxiclav, had any functional impairment than did those whose mothers had received no erythromycin (658 [42.3%] of 1554 children vs 574 [38.3%] of 1498; odds ratio 1.18, 95% CI 1.02-1.37). Co-amoxiclav (with or without erythromycin) had no effect on the proportion of children with any functional impairment, compared with receipt of no co-amoxiclav (624 [40.7%] of 1523 vs 608 [40.0%] of 1520; 1.03, 0.89-1.19). No effects were seen with either antibiotic on the number of deaths, other medical conditions, behavioural patterns, or educational attainment. However, more children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [3.3%] of 1611 vs 27 [1.7%] of 1562, 1.93, 1.21-3.09; co-amoxiclav: 50 [3.2%] of 1587 vs 30 [1.9%] of 1586, 1.69, 1.07-2.67). The number needed to harm with erythromycin was 64 (95% CI 37-209) and with co-amoxiclav 79 (42-591). INTERPRETATION: The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low. FUNDING: UK Medical Research Council.

Culex nigripalpus: seasonal shift in the bird-mammal feeding ratio in a mosquito vector of human encephalitis.

Blood-engorged Culex nigripalpus (Theob.) collected throughout the year in two Florida localities were serologically tested to determine the host range of this mosquito in nature. A proportional increase in feeding on mammals occurred in early summer, reached a maximum between July and October, and was followed by a shift back to avian hosts which dominated the feeding pattern during winter and spring. This finding strengthens the hypothesis that a biphasic pattern of feeding is a basic characteristic of an enzootic vector that, in epidemic years, also serves as the primary vector of avian arbovirus to man.

Late termination of pregnancy: a comparison of obstetricians' experience in eight European countries.

OBJECTIVE: To compare the experience and attitude of obstetricians in Europe towards late termination of pregnancy and the factors affecting their responses. DESIGN: Cluster sampling cross-sectional survey. All neonatal intensive care unit (NICU)-associated maternity units were recruited (census sampling) in Luxembourg, the Netherlands and Sweden. In France, Germany, Italy, Spain and the UK, units were selected at random. In every recruited unit, all obstetricians with at least 6 months' experience were invited to participate. SETTING: NICU-associated maternity units in eight European countries. POPULATION: Obstetricians with at least 6 months' clinical experience. METHODS: An anonymous, self-administered questionnaire was used. Multinomial logistic analysis was used to identify factors predicting the obstetricians' views about modifying the law governing late termination in their country. MAIN OUTCOME MEASURE: Obstetricians' experience of late termination of pregnancy and views about national policies. RESULTS: One hundred and five units and 1530 obstetricians participated (response rates 70 and 77% respectively). The most common indications for late termination were congenital anomalies and women's physical health. Feticide was not common except in France, Luxembourg and the UK. Active euthanasia of a liveborn was practiced in France and the Netherlands. Obstetricians in Germany were more likely to feel that late termination should be more severely restricted, the opposite was true in Spain and the Netherlands. In Italy, there was dissatisfaction with current status, but opinion was divided, reflecting views on both sides of the debate. CONCLUSIONS: This research outlines current practice in a difficult and sensitive area and suggests the need for more discussion and support for all those who were involved.

Assessing techniques for disinfecting sites for inserting intravenous catheters into the jugular veins of horses.

The sites of insertion of catheters into the jugular veins of six horses were investigated to determine common isolates and to assess the effectiveness of two disinfection protocols with the hair coat left long, clipped or shaved. Skin commensals (Staphylococcus, Streptococcus and Micrococcus species) and environmental contaminants (Bacillus, Enterobacteriaceae, Aspergillus and Mucor species) were the microorganisms most frequently isolated. Chlorhexidine gluconate and povidone-iodine-based skin disinfection protocols resulted in significant reductions in the number of bacterial isolates from clipped sites. With chlorhexidine, there were no significant differences between the reductions observed at sites with the hair coat left long, clipped or shaved.

Assessment of subclinical venous catheter-related diseases in horses and associated risk factors.

A total of 102 horses that had a catheter introduced intravenously to facilitate treatment had the catheterised jugular vein and contralateral vein examined by ultrasound every 48 hours. Subclinical complications were defined by thrombus formation or thickening of the venous wall, and the data were analysed to establish risk factors for the development of these complications. The horses with a rectal temperature above 38.5 degrees C when the catheter was introduced were four times more likely to develop complications, than the horses with a lower temperature. The administration of a NSAID while the catheter was in place reduced the risk of complications developing.

Factors associated with cross-contamination of hides of Scottish cattle by Escherichia coli O157.

The putative source of hide contamination for 236 cattle in Scotland followed from the farm through to slaughter was determined using phage and verocytotoxin type data. The majority of cattle (84%) were found to have subtypes of Escherichia coli O157 on their hide that had not been found previously in any animal from the farm of origin, strongly suggesting that contamination occurred once animals had left the farm of origin. Using logistic regression analysis, several variables and factors were found to be strongly associated (P < 0.01) with cross-contamination of cattle hides at the univariate level; commercial transport to slaughter, transport with other animals, use of a crush, line automation, and increasing slaughterhouse throughput were all risk factors, while feeding hay in lairage, processing an animal earlier in a slaughter cohort, and cleaning the landing area poststunning were protective. In the multivariable model, with the slaughterhouse and the farm group included as random effects, factors associated with the cross-contamination of cattle hides were identified. Transport to the slaughterhouse by a commercial hauler had a borderline-significant association with increased odds of an animal having a cross-contaminated hide (odds ratio [OR] [95% confidence interval (CI)] = 5.7 [0.99, 33.0]; P = 0.05). At the slaughterhouse, providing hay to cattle waiting in lairage (OR [95% CI] = 0.04 [<0.01, 1.04]; P = 0.05) and cleaning the landing area (OR [95% CI] = 0.03 [<0.01, 1.15,]; P = 0.06) also had a borderline-significant association with decreased odds of an animal having a cross-contaminated hide. Although the prevalence of carcass contamination remains very low, targeted intervention at the preslaughter stage may have the potential to reduce further the risk to public health.

Mechanics of airflow in the human nasal airways.

The mechanics of airflow in the human nasal airways is reviewed, drawing on the findings of experimental and computational model studies. Modelling inevitably requires simplifications and assumptions, particularly given the complexity of the nasal airways. The processes entailed in modelling the nasal airways (from defining the model, to its production and, finally, validating the results) is critically examined, both for physical models and for computational simulations. Uncertainty still surrounds the appropriateness of the various assumptions made in modelling, particularly with regard to the nature of flow. New results are presented in which high-speed particle image velocimetry (PIV) and direct numerical simulation are applied to investigate the development of flow instability in the nasal cavity. These illustrate some of the improved capabilities afforded by technological developments for future model studies. The need for further improvements in characterising airway geometry and flow together with promising new methods are briefly discussed.

Experimental investigation of nasal airflow.

The airway geometry of the nasal cavity is manifestly complex, and the manner in which it controls the airflow to accomplish its various physiological functions is not fully understood. Since the complex morphology and inaccessibility of the nasal passageways precludes detailed in-vivo measurements, either computational simulation or in-vitro experiments are needed to determine how anatomical form and function are related. The fabrication of a replica model of the nasal cavity, of a high optical clarity and derived from in-vivo scan data is described here, together with characteristics of the flow field investigated using particle image velocimetry (PIV) and flow visualization. Flow visualization is shown to be a capable and convenient technique for identifying key phenomena. Specifically the emergence of the jet from the internal nasal valve into the main cavity, how it impacts on the middle turbinate, and the large enhancement of dispersion that accompanies the initial appearance of flow instability are revealed as particularly significant features. The findings from the visualization experiments are complemented by PIV imaging, which provides quantitative detail on the variations in velocity in different regions of the nasal cavity. These results demonstrate the effectiveness of the cavity geometry in partitioning the flow into high shear zones, which facilitate rapid heat transfer and humidification from the nasal mucosa, and slower zones affording greater residence times to facilitate olfactory sensing. The experimental results not only provide a basis for comparison with other computational modelling but also demonstrate an alternative and flexible means to investigate complex flows, relevant to studies in different parts of the respiratory or cardiovascular systems.

Polymer/surfactant interactions at the air/water interface.

The development of neutron reflectometry has transformed the study and understanding of polymer/surfactant mixtures at the air/water interface. A critical assessment of the results from this technique is made by comparing them with the information available from other techniques used to investigate adsorption at this interface. In the last few years, detailed information about the structure and composition of adsorbed layers has been obtained for a wide range of polymer/surfactant mixtures, including neutral polymers and synthetic and naturally occurring polyelectrolytes, with single surfactants or mixtures of surfactants. The use of neutron reflectometry together with surface tensiometry, has allowed the surface behaviour of these mixtures to be related directly to the bulk phase behaviour. We review the broad range of systems that have been studied, from neutral polymers with ionic surfactants to oppositely charged polyelectrolyte/ionic surfactant mixtures. A particular emphasis is placed upon the rich pattern of adsorption behaviour that is seen in oppositely charged polyelectrolyte/surfactant mixtures, much of which had not been reported previously. The strong surface interactions resulting from the electrostatic attractions in these systems have a very pronounced effect on both the surface tension behaviour and on adsorbed layers consisting of polymer/surfactant complexes, often giving rise to significant surface ordering.

Risk factors for hide contamination of Scottish cattle at slaughter with Escherichia coli O157.

In the slaughter processing of cattle, contaminated hides have been identified as one of the major sources of Escherichia coli O157 carcase contamination. Logistic regression analysis was applied to data collected in a large scale study in Scotland involving 222 cattle forming 34 groups sent for slaughter from 30 farms to 10 slaughterhouses. Aspects of individual animal characteristics, farm management practices and slaughterhouse features were examined to identify potential risk factors for hide contamination at harvest. Two models were developed, the first in which slaughterhouse was modelled as a fixed effect, and a second model where slaughterhouse and farm groups were modelled as random effects. In the first model, there was a significantly increased risk of a carcase testing positive for E. coli O157 on the hide if either the hide of the carcase immediately before or after it on the line was contaminated (OR 3.6; 95% CI: 1.4-9.9). If both adjacent carcases had contaminated hides, the odds ratio for the study carcase having a contaminated hide rose to 11.5 (95% CI: 4.4-32.5). If animals were held in lairage, receiving hay as feed appeared to have a protective effect on hide contamination. Transportation to the slaughterhouse by haulier, as opposed to transport by the farmer, was associated with a 5.4 increase in the odds of E. coli O157 contamination. The use of a crush in the lairage, often employed when reading ear tags, was also found to significantly increase the odds of hide contamination with E. coli O157. In the second model, the inclusion of slaughterhouse and farm group as random effects resulted in two of the previously identified factors being associated with hide contamination. If at least one of the adjacent carcases on the line had a contaminated hide, the associated odds ratio was 6.6 (95% CI: 2.8-15.9), which rose to 22.7 (95% CI: 9.3-55.5) if both adjacent hides were contaminated. Receiving hay in lairage was found to be important to the model, although not significant in itself (OR 0.005; 95% CI: 1.2e(-6)-20.7). These results suggest that modifiable risk factors for hide contamination exist. However, in order best to reduce the prevalence of hide contamination at slaughter, individual slaughterhouse risk assessment and intervention strategies are appropriate.

Effects of cancer chemotherapeutic agents on endocrine organs and serum levels of estrogens, progesterone, prolactin, and luteinizing hormone.

The effects of the following cancer chemotherapeutic agents on serum hormonal levels, estrous cycles, and endocrine organs were studied in mature, normal Sprague-Dawley rats by radioimmunoassay, vaginal smear examination, and organ weight end point: estradiol mustard (NSC 112259), testosterone mustard (NSC 112260), phenoestrin (NSC 104469), methotrexate (NSC 740), 5-fluorouracil (NSC 19893), vinblastine (NSC 49842), vincristine (NSC 67574), nitrogen mustard (NSC 762), and 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC 409962). Following 2 weeks of treatment, estradiol-17beta levels were markedly elevated by all compounds except testosterone mustard and nitrogen mustard, which caused a decrease. Estrone levels were elevated by methotrexate, 5-fluorouracil, vinblastine, vincristine, nitrogen mustard, and 1,3-bis(2-chloroethyl)-1-nitrosourea, but were lowered by estradiol mustard. Progesterone levels were elevated only by estradiol mustard and testosterone mustard and were not affected by other compounds. Prolactin surge during proestrus was suppressed by phenesterin and methotrexate. Luteinizing hormone levels were lowered by methotrexate and nitrogen mustard. Estrous cycles of rats treated with estradiol mustard were arrested at proestrus, and the uterine and pituitary weights of these rats markedly increased. Uterine weight loss was significant following treatment with testosterone mustard, 5-fluorouracil, and nitrogen mustard. Thyroid weight was reduced by all compounds except methotrexate and vinblastine. Significant increases in pituitary weights occurred following treatment with all compounds except 1,3-bis(2-chloroethyl)-1-nitrosourea. The effects on ovarian and adrenal weights were minimal although significant by some compounds. Thus, in addition to their direct antitumor effects, these agents also produced changes in endocrine system which may be synergistic or antagonistic to the chemotherapy of endocrine-responsive neoplasms.

A phase I study of the left-shifting agent BW12C79 plus mitomycin C and the effect on the skeletal muscle metabolism using 31P magnetic resonance spectroscopy.

BW12C79 stabilizes the oxyhemoglobin molecule resulting in a reversible left-shift of the oxygen saturation curve. The activity of a number of bioreductive anticancer drugs, such as mitomycin C, may be enhanced under hypoxic conditions. Twenty-four patients with various malignancies received BW12C79 and mitomycin C. BW12C79 was administered i.v. with a loading dose (20-50 mg/kg) over 1 h followed by a maintenance infusion of 4 mg/kg/h for 5 h. Percentage modification of the oxyhemoglobin (degree of left-shift) was dose related with maximum modification of 56% and was maintained for the duration of maintenance infusion of BW12C79. Hemoglobin electrophoresis showed a fast moving band consistent with the BW12C79-oxyhemoglobin complex. Side effects at the top dose level comprised headache, nausea/vomiting, vein irritation, and myocardial ischemia. One other patient suffered from an acute encephalopathy of unknown etiology a few days following BW12C79. 31P magnetic resonance spectroscopy of exercising calf muscles showed increased breakdown of high energy phosphate stores and a greater reduction in pH. Recovery of the high energy phosphate stores after exercise was slow. These results were consistent with reduced oxygen supply due to either a left shift of the oxygen saturation curve and/or reduced muscle blood flow. BW12C79 did not interfere with the pharmacokinetics of mitomycin C. In conclusion, this phase I study demonstrates the feasibility of achieving a significant left shift in the oxygen saturation curve in cancer patients which is maintained for at least 5 h with acceptable toxicity. The maximum tolerated dose of BW12C79 was 50 mg/kg loading infusion followed by a maintenance infusion of 4 mg/kg/h. Magnetic resonance spectroscopy results were consistent with reduced supply of oxygen to exercising skeletal muscle. BW12C79 may be of potential benefit as an adjunct to bioreductive drugs in the treatment of solid tumors.

Assessment of mitochondrial function and control in normal and diseased states.

Mitochondrial function in muscle in vivo can be quantitatively evaluated using 31-phosphorus nuclear magnetic resonance. In resting muscle, the concentrations of ions (e.g. H+, Na+) and two of the major bioenergetic components (inorganic phosphate and creatine) are determined by regulated transcellular transport processes. During recovery after exercise the kinetics and control of mitochondrial ATP synthesis can be established. During exercise the relative contributions to ATP synthesis of phosphocreatine (using creatine kinase), anaerobic glycogenolysis and oxidative phosphorylation are dissected and have been shown to change with time. The consequences of mitochondrial lesions and dysfunctions on these processes have been summarised.