CO2 storage and release in the deep Southern Ocean on millennial to centennial timescales.

The cause of changes in atmospheric carbon dioxide (CO2) during the recent ice ages is yet to be fully explained. Most mechanisms for glacial-interglacial CO2 change have centred on carbon exchange with the deep ocean, owing to its large size and relatively rapid exchange with the atmosphere1. The Southern Ocean is thought to have a key role in this exchange, as much of the deep ocean is ventilated to the atmosphere in this region2. However, it is difficult to reconstruct changes in deep Southern Ocean carbon storage, so few direct tests of this hypothesis have been carried out. Here we present deep-sea coral boron isotope data that track the pH-and thus the CO2 chemistry-of the deep Southern Ocean over the past forty thousand years. At sites closest to the Antarctic continental margin, and most influenced by the deep southern waters that form the ocean's lower overturning cell, we find a close relationship between ocean pH and atmospheric CO2: during intervals of low CO2, ocean pH is low, reflecting enhanced ocean carbon storage; and during intervals of rising CO2, ocean pH rises, reflecting loss of carbon from the ocean to the atmosphere. Correspondingly, at shallower sites we find rapid (millennial- to centennial-scale) decreases in pH during abrupt increases in CO2, reflecting the rapid transfer of carbon from the deep ocean to the upper ocean and atmosphere. Our findings confirm the importance of the deep Southern Ocean in ice-age CO2 change, and show that deep-ocean CO2 release can occur as a dynamic feedback to rapid climate change on centennial timescales.

Dichotomy between Regulation of Coral Bacterial Communities and Calcification Physiology under Ocean Acidification Conditions.

Ocean acidification (OA) threatens the growth and function of coral reef ecosystems. A key component to coral health is the microbiome, but little is known about the impact of OA on coral microbiomes. A submarine CO2 vent at Maug Island in the Northern Mariana Islands provides a natural pH gradient to investigate coral responses to long-term OA conditions. Three coral species (Pocillopora eydouxi, Porites lobata, and Porites rus) were sampled from three sites where the mean seawater pH is 8.04, 7.98, and 7.94. We characterized coral bacterial communities (using 16S rRNA gene sequencing) and determined pH of the extracellular calcifying fluid (ECF) (using skeletal boron isotopes) across the seawater pH gradient. Bacterial communities of both Porites species stabilized (decreases in community dispersion) with decreased seawater pH, coupled with large increases in the abundance of Endozoicomonas, an endosymbiont. P. lobata experienced a significant decrease in ECF pH near the vent, whereas P. rus experienced a trending decrease in ECF pH near the vent. In contrast, Pocillopora exhibited bacterial community destabilization (increases in community dispersion), with significant decreases in Endozoicomonas abundance, while its ECF pH remained unchanged across the pH gradient. Our study shows that OA has multiple consequences on Endozoicomonas abundance and suggests that Endozoicomonas abundance may be an indicator of coral response to OA. We reveal an interesting dichotomy between two facets of coral physiology (regulation of bacterial communities and regulation of calcification), highlighting the importance of multidisciplinary approaches to understanding coral health and function in a changing ocean.IMPORTANCE Ocean acidification (OA) is a consequence of anthropogenic CO2 emissions that is negatively impacting marine ecosystems such as coral reefs. OA affects many aspects of coral physiology, including growth (i.e., calcification) and disrupting associated bacterial communities. Coral-associated bacteria are important for host health, but it remains unclear how coral-associated bacterial communities will respond to future OA conditions. We document changes in coral-associated bacterial communities and changes to calcification physiology with long-term exposure to decreases in seawater pH that are environmentally relevant under midrange IPCC emission scenarios (0.1 pH units). We also find species-specific responses that may reflect different responses to long-term OA. In Pocillopora, calcification physiology was highly regulated despite changing seawater conditions. In Porites spp., changes in bacterial communities do not reflect a breakdown of coral-bacterial symbiosis. Insights into calcification and host-microbe interactions are critical to predicting the health and function of different coral taxa to future OA conditions.

Barriers and facilitators towards fertility preservation care for cancer patients: a meta-synthesis.

Infertility is a potential late-effect of cancer treatment, which negatively impact on young cancer survivors' quality of life. This paper aims to synthesise factors that influence patients', carers' and healthcare professionals' decision to engage in fertility preservation programmes at the time of cancer diagnosis. Four databases and grey literature were systematically searched to identify qualitative and mixed-method studies published between 2000 and 2015. Thematic framework and synthesis were used to analyse and synthesise the data. Thirty-seven papers were selected and represented. Factors that affect engagement of patients, carers and healthcare providers in fertility preservation care can be grouped as intrinsic and extrinsic. Intrinsic factors include patients' attitudes, health beliefs and health literacy; clinicians' approaches and skills; as well as doctor-patient relationships. Extrinsic factors include fertility preservation care resources and institutional characteristics. We conclude that existing qualitative literature highlights the complex convergences of intrinsic and extrinsic factors that impede successful engagement in fertility preservation care. Addressing these factors could help cancer survivors achieve better health outcomes and improve their wellbeing. Potential solutions include attitudinal changes and organisational skill reforms across the health community that will help ensure a person's goals are always at the centre of their cancer care.

[Types of pain coping in chronic pain patients]. / Typen der Schmerzverarbeitung bei Patienten mit chronischen Schmerzen.

BACKGROUND: The characterization of subtypes of chronic pain patients based on their pain coping profiles may contribute to a better understanding of the pain syndrome, to more specific indications of established treatment options as well as to further development of therapeutic interventions. OBJECTIVE: The aim of this study was to examine whether different subgroups of chronic pain patients emerge when using the German pain coping questionnaire (FESV) to identify homogeneous subgroups of pain coping patterns. Furthermore, the aim was to examine whether these pain coping subgroups differ in terms of sociodemographic characteristics, as well as pain and treatment-related aspects. MATERIAL AND METHODS: A total of 166 inpatients with a chronic pain disorder according to ICD-10 F45.41 were examined as part of the routine assessment within an interdisciplinary pain treatment program. Cognitive and behavioral pain coping and pain-related psychological impairment were measured with the FESV as components of pain coping. Using cluster analyses, homogeneous patient subgroups were generated on the basis of pain coping data. The resulting subgroups were subsequently compared regarding sociodemographic characteristics, pain-related impairment, global psychological distress, depression, anxiety, perceived stress, utilization of social support and motivation for psychotherapy. RESULTS AND CONCLUSION: The results revealed three distinct subgroups regarding pain coping patterns: (1) high impairment and high coping, (2) low impairment and high coping and (3) high impairment and low coping. The subgroups differed significantly in almost all characteristics, except for pain duration and pain intensity. The categorization into the abovementioned pain coping subtypes may assist clinicians in tailoring pain treatment to the needs and characteristics of the individual patients.

Hemiparasitic plant impacts animal and plant communities across four trophic levels.

Understanding the impact of species on community structure is a fundamental question in ecology. There is a growing body of evidence that suggests that both subdominant species and parasites can have disproportionately large effects on other organisms. Here we report those impacts for a species that is both subdominant and parasitic, the hemiparasite Rhinanthus minor. While the impact of parasitic angiosperms on their hosts and, to a lesser degree, coexisting plant species, has been well characterized, much less is known about their effects on higher trophic levels: We experimentally manipulated field densities of the hemiparasite Rhinanthus minor in a species-rich grassland, comparing the plant and invertebrate communities in plots where it was removed, present at natural densities, or present at enhanced densities. Plots with natural and enhanced densities of R. minor had lower plant biomass than plots without the hemiparasite, but enhanced densities almost doubled the abundance of invertebrates within the plots across all trophic levels, with effects evident in herbivores, predators, and detritivores. The hemiparasite R. minor, despite being a subdominant and transient component within plant communities that it inhabits, has profound effects on four different trophic levels. These effects persist beyond the life of the hemiparasite, emphasizing its role as a keystone species in grassland communities.

Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer.

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy.

Preterm infant with necrotizing enterocolitis and arteritis secondary to streptococcus gallolyticus subspecies pasteurianus.

 Streptococcus gallolyticus subspecies pasteurianus is a subtype of Streptococcus bovis (S. bovis) that has become increasingly recognized as a sepsis-causing pathogen in neonates. It is well documented that S. bovis species have a predilection to both cardiac and gastrointestinal tissue, and in adult populations, isolating these organisms in the bloodstream often triggers further evaluation for co-morbid complications such as colon cancer or endocarditis. However, no such guidance currently exists in neonatal literature. We present a case of a preterm infant with S. gallolyticus subsp. pasteurianus bacteremia presenting as necrotizing enterocolitis (NEC) not previously described in the literature. Furthermore, through a complete diagnostic evaluation, including an echocardiogram, our patient was found to have the rare complication of endocarditis.

Prolonged cycling lowers subsequent running mechanical efficiency in collegiate triathletes.

BACKGROUND: A significant challenge that non-elite collegiate triathletes encounter during competition is the decline in running performance immediately after cycling. Therefore, the purpose of this study was to determine if performing a 40-km bout of cycling immediately before running would negatively influence running economy and mechanical efficiency of running during simulated race conditions in collegiate triathletes. METHODS: Eight competitive club-level collegiate triathletes randomly performed two trials: cycling for 40 km (Cycle-Run) or running for 5 km (Run-Run), immediately followed by a four-minute running economy and mechanical efficiency of running test at race pace on an instrumented treadmill. Blood lactate, respiratory exchange ratio, mechanical work, energy expenditure, and muscle glycogen were also measured during the four-minute running test. RESULTS: Mechanical efficiency of running, but not running economy, was significantly lower in Cycle-Run, compared to Run-Run (42.1 ± 2.5% vs. 48.1 ± 2.5%, respectively; p = 0.027). Anaerobic energy expenditure was significantly higher in the Cycle-Run trial, compared to the Run-Run trial (16.3 ± 2.4 vs. 7.6 ± 1.1 kJ; p = 0.004); while net (151.0 ± 12.3 vs. 136.6 ± 9.6 kJ; p = 0.204) and aerobic energy expenditure (134.7 ± 12.3 vs. 129.1 ± 10.5 kJ; p = 0.549) were not statistically different between trials. Analysis of blood lactate, respiratory exchange ratio, mechanical work, and changes in muscle glycogen revealed no statistically significant differences between trials. CONCLUSIONS: These results suggest that mechanical efficiency of running, but not running economy, is decreased and anaerobic energy expenditure is increased when a 40-km bout of cycling is performed immediately before running in collegiate triathletes.

Noninvasive Neuromonitoring of Hypothermic Circulatory Arrest in Aortic Surgery.

BACKGROUND AND AIMS: Circulatory arrest carries a high risk of neurological damage, but modern monitoring methods lack reliability, and is susceptible to the generalized effects of both anesthesia and hypothermia. The objective of this prospective, explorative study was to research promising, reliable, and noninvasive methods of neuromonitoring, capable of predicting neurological outcome after hypothermic circulatory arrest. MATERIALS AND METHODS: Thirty patients undergoing hypothermic circulatory arrest during surgery of the thoracic aorta were recruited in a single center and over the course of 4 years. Neuromonitoring was performed with a four-channel electroencephalogram montage and a near-infrared spectroscopy monitor. All data were tested off-line against primary neurological outcome, which was poor if the patient suffered a significant neurological complication (stroke, operative death). RESULTS: A poor primary neurological outcome seen in 10 (33%) patients. A majority (63%) of the cases were emergency surgery, and thus, no neurological baseline evaluation was possible. The frontal hemispheric asymmetry of electroencephalogram, as measured by the brain symmetry index, predicted primary neurological outcome with a sensitivity of 79 (interquartile range; 62%-88%) and specificity of 71 (interquartile range; 61%-84%) during the first 6 h after end of circulatory arrest. CONCLUSION: The hemispheric asymmetry of frontal electroencephalogram is inherently resistant to generalized dampening effects and is predictive of primary neurological outcome. The brain symmetry index provides an easy-to-use, noninvasive neuromonitoring method for surgery of the thoracic aorta and postoperative intensive care.

Swallow syncope: reflex or reflux?

A 51-year-old man presented with symptoms of syncope on consuming solid foods. He had a 5 year history of intermittent symptoms on eating only solids and his cardiovascular investigations revealed bradycardia during food ingestion. He was treated by insertion of a pacemaker with cessation of his syncopal symptoms.

Physician attitudes regarding prostaglandin treatment for glaucoma in the United States and Europe.

PURPOSE: To evaluate physician use of prostaglandins (latanoprost, travoprost, and bimatoprost) in the United States (US) and Europe (EU). METHODS: One thousand multiple-choice surveys were distributed via e-mail in the US and EU. RESULTS: The authors received 71 responses (US 40 [8%] and EU 31 [6%]). Physicians preferred prostaglandin monotherapy (US 39 [98%] and EU 22 [71%], p=0.003), usually latanoprost (US 32 [80%] and EU 22 [71%], p=0.45). When more efficacy was required, US physicians would typically switch (23 [58%]) and EU physicians would add therapy (22 [71%], p=0.007). In both continents 45% of respondents stated bimatoprost was more efficacious. CONCLUSIONS: US and EU physicians prefer prostaglandin monotherapy, most commonly latanoprost. Bimatoprost is often perceived as more effective, but having a higher incidence of conjunctival hyperemia.

Comparison of daytime efficacy and safety of dorzolamide/timolol maleate fixed combination versus latanoprost.

PURPOSE: To compare the 12-hour efficacy and safety of dorzolamide/timolol fixed combination (DTFC) dosed twice daily versus latanoprost dosed every evening following a timolol run-in in primary open-angle glaucoma patients. METHODS: Following a 6-week timolol run-in patients were randomized to either DTFC or latanoprost for 6 weeks and then changed to the opposite treatment for 6 weeks. At the end of the run-in, and the end of each treatment period, the intraocular pressure (IOP) was measured every 2 hours between 8:00 AM and 8:00 PM. RESULTS: Thirty-one patients completed at least one time point in both treatment periods. Both treatments reduced the IOP for the diurnal curve, and at each time point, from the timolol run-in baseline (p<0.0001). The 12-hour IOP on timolol was 22.1+/-2.8 mmHg, whereas on DTFC it was 18.1+/-2.8 and latanoprost 18.3+/-3.1 mmHg (p=0.4). Further, there was no statistical difference in IOP between treatments at any time point (p< or =0.1). There was no statistical difference for any individual adverse event between treatments (p>0.05). CONCLUSIONS: This study suggests that following a timolol run-in both DTFC and latanoprost provide comparable daytime efficacy and safety.

Long-term progression at individual mean intraocular pressure levels in primary open-angle and exfoliative glaucoma.

PURPOSE: To describe progression and non-progression rates at individual mean intraocular pressure (IOP) levels for patients with primary open-angle and exfoliative glaucoma. METHODS: A meta-analysis of five previously published retrospective studies describing progression and non-progression rates at individual intraocular pressure levels over 5 or more years of follow-up. All patients had primary open-angle (four studies) or exfoliative glaucoma (one study). RESULTS: This meta-analysis included 822 patients of whom 655 (80%) had primary openangle glaucoma and 167 (20%) had exfoliative glaucoma. In total, 220 patients progressed (27%), while 602 (73%) remained stable over 5 years. The mean IOP was 20.0 for progressed and 17.1 mmHg for stable patients (p=0.0004). The peak IOP was 29.1 for progressed and 23.6 mmHg for stable patients (p=0.0014). At an IOP level >18 mmHg, 49% of patients remained stable; at 18 mmHg, 78%; between 13 and 17 mmHg, 82%; and <13 mmHg, 96%. Additional factors associated with progression were older age (p=0.0004) and exfoliative glaucoma (p=0.0001). However, multivariant regression analysis identified only mean IOP as a risk factor for progression (p=0.039). CONCLUSIONS: This study suggests that maintaining an IOP well within the normal range over 5 years in patients with primary open-angle or exfoliative glaucoma helps to prevent glaucomatousprogression.

Long-Term Survival and Quality of Life After Hypothermic Circulatory Arrest in Aortic Surgery.

BACKGROUND AND AIMS:: Hypothermic circulatory arrest carries a high risk of mortality and neurological complications. An important part of assessing surgical treatment is the evaluation of long-term survival and postoperative health-related quality of life. MATERIAL AND METHODS:: In this prospective study, 30 patients undergoing hypothermic circulatory arrest during surgery of the thoracic aorta, and 31 comparison patients undergoing elective coronary artery surgery without hypothermic circulatory arrest were evaluated for long-term survival and health-related quality of life, using the RAND 36-Item Health Survey questionnaire. The results were compared to national age- and sex-matched reference populations of the chronically ill and healthy adults. RESULTS:: After 4.6-8.0 years, available study (88%) and comparison (59%) patients were interviewed. The life expectancy was similar with 4- and 8-year survival of 90%, and 87% for the study group, and 94%, and 94% for the comparison group, respectively (log rank test, p = 0.62). The RAND-36 scores for study and comparison groups were congruent in all dimensions, describing physical, mental, and social domains. The study patients' health-related quality of life results were similar to the national reference population with chronic illnesses. CONCLUSION:: After hypothermic circulatory arrest, patients undergoing surgery of the thoracic aorta achieve a similar long-term life expectancy and health-related quality of life as do patients undergoing coronary surgery without hypothermic circulatory arrest, and a health-related quality of life similar to the national reference population with chronic illnesses. These results justify operative treatment in this high-risk patient population.

Estimating the risks of ovarian hyperstimulation syndrome (OHSS): implications for egg donation for research.

This study aims to provide an estimate of women's risk of ovarian hyperstimulation syndrome (OHSS) when undergoing superovulation to donate eggs for research. This is an essential prerequisite for appropriate informed consent. In the absence of sufficiently large numbers of egg donors to assess the risk, comparative data was obtained from women undergoing the same superovulation protocol for in vitro fertilization (IVF) treatment. In this prospective study 339 women, who developed >/=20 follicles after superovulation in their first treatment cycle (total number of treatment cycles during the same period - 2417), were intensively monitored on five occasions, between human chorionic gonadotrophin and pregnancy test, according to our routine clinical protocol. Hospital admission was needed for 49 (14.5%) women, 13 (3.8%) needed intravenous fluids and 9 (2.7%) needed paracentesis. The admission rates were similar in pregnant and non-pregnant women (13.5% vs. 15%); the need for intravenous fluids and paracentesis were 3.2% vs. 2.3% and 6.3% vs. 2.3%, respectively. The peak increase in haematocrit occurred on Day 4 after hCG, and the mean day of hospital admission was Day 5. If an egg donor develops <20 follicles, she can be reassured that the risk of OHSS is very small (<0.1%). If >/=20 follicles develop, her risk of hospital admission due to OHSS is <15%. The absence of pregnancy in egg donors does not eliminate the risk of OHSS. Given the timescale of development of the haematological and biochemical abnormalities, egg donors who develop >/=20 follicles should be actively monitored for the first week after egg collection.

B16 murine melanoma and aging: slower growth and longer survival in old mice.

The growth characteristics and colonization potential of a transplantable melanoma administered to young (3 mo) and old (24 mo) C57BL/6 mice were investigated. After sc injection of B16-F10 melanoma cells, tumor growth was slower, and final tumor volume was less in the older mice. Furthermore, after iv injection of B16-F1 melanoma cells, the number of pulmonary colonies was also less, and the survival was greater in the older mice. These findings indicate an age advantage in this experimental tumor model that may be attributed to either physical or immunologic factors.

Assessment of bleomycin lung toxicity using angiotensin-converting enzyme in pulmonary lavage.

Activity of the dipeptidyl hydrolase angiotensin-converting enzyme has been observed to be altered by treatment with bleomycin. We used an animal model of bleomycin lung toxicity to study the effects on angiotensin-converting enzyme activity in various lung fractions. Serum activity of angiotensin-converting enzyme increased only 23% after a single intratracheal instillation of bleomycin. Lung tissue angiotensin-converting enzyme activity fell to 40% of control level (p < 0.05) and returned toward and eventually exceeded control values during the ensuing 6 weeks. However, angiotensin-converting enzyme activity in alveolar lavage fluid from bleomycin-treated rats was elevated 30-fold above the barely detectable levels found in control animals. Angiotensin-converting enzyme activity in lavage fluid was soluble and was not associated with the alveolar cell pellet. Maximum elevation of lavage angiotensin-converting enzyme activity occurred 3 days following bleomycin instillation. Significant transudation of serum into alveolar lavage fluid occurred in bleomycin-treated rats. Nevertheless, this phenomenon would not explain the high levels of angiotensin-converting enzyme activity found in lavage fluid. Elevated lavage angiotensin-converting enzyme levels were detected after doses of bleomycin too low to cause significant sequelae of pulmonary fibrosis. Lavage angiotensin-converting enzyme is a sensitive monitor of tissue response to bleomycin.

Phase I trial of intraperitoneal recombinant interleukin-2/lymphokine-activated killer cells in patients with ovarian cancer.

Ten patients with ovarian cancer refractory to conventional therapy were treated with intraperitoneal (i.p.) recombinant interleukin-2 (rIL-2) and lymphokine-activated killer cells (LAK). The 28-day protocol consisted of 6 priming i.p. rIL-2 infusions on days 0, 4, 6, 8, 10, and 12. Leukapheresis was performed for mononuclear cell collection on days 15, 16, 17, and 18 and lymphokine-activated killer cells were given i.p. with the rIL-2 on days 19 and 21. Three additional i.p. rIL-2 infusions were given on days 23, 25, and 27. Three dose levels of rIL-2 were tested: 5 X 10(5), 2 X 10(6), and 8 X 10(6) units/m2 body surface area. The dose-limiting toxicity was abdominal pain secondary to ascites accumulation with significant weight gain. Other toxic effects included decreased performance status, fever, nausea and vomiting, diarrhea, and anemia. Peripheral lymphocytosis and eosinophilia were seen at all dose levels. The maximum tolerated dose is 8 X 10(6) units/m2/dose. Peripheral and peritoneal IL-2 levels were measured with a bioassay using an IL-2-dependent cell line. At the highest dose level, serum IL-2 was greater than 10 units/ml for 18 h. After the first infusion, a 2-log dilution of the i.p. IL-2 was measured in the serum. In the postleukapheresis i.p. IL-2-dosing period less IL-2 was detected in the serum than in the earlier i.p. IL-2-priming period. The induction and persistence of LAK activity were studied. Peritoneal LAK activity was detected as early as 4 days after the first i.p. infusion, by day 11 in all evaluable patients, and persisted for the 6-day interval between priming IL-2 and LAK/IL-2 infusion. Peritoneal lytic activity persisted until day 28 in 5 tested patients. These peritoneal cells retained lytic activity 48 h in culture medium without rIL-2 present. Peritoneal LAK activity correlated with the percentage of mononuclear cells and the percentage of CD56-positive mononuclear cells in the peritoneum. The yield of peripheral lymphocytes after the six i.p. priming doses of rIL-2 correlated with the dose level of rIL-2 infused. Peripheral blood LAK activity showed a minimal, however progressive, increase during the treatment protocol. LAK activity could be enhanced if rIL-2 was present during the 4-h assay. These studies indicate that i.p. rIL-2 infusion induced durable regional LAK activity and primes peripheral blood cells for LAK activity if exposed briefly to additional IL-2.

Phase I clinical and pharmacokinetic study of trimetrexate using a daily x5 schedule.

Trimetrexate (TMQ; NSC 352122) is a potent inhibitor of dihydrofolate reductase with good activity against murine i.p.-implanted B16 melanoma and colon 26 tumors. Preclinical antineoplastic activity, demonstrated schedule dependency, and data suggesting effectiveness against methotrexate-resistant cells prompted a Phase I clinical and pharmacokinetic study of trimetrexate using an i.v. daily x5 schedule. Forty-three good performance status patients were treated with 12 dose levels using daily doses varying from 0.5 to 15 mg/m2/d. Plasma and urine samples were obtained for pharmacokinetic analysis using a high-performance liquid chromatographic method. Myelosuppression was dose limiting and 15 mg/m2/d x5 was the maximum tolerated dose. White blood cell (WBC) and platelet toxicity were noted at doses of 1.6 mg/m2 and above. Median WBC and platelet nadirs occurred on approximately Days 11-12 with recovery by Days 15-18. Nonhematological toxicity included mucositis, nausea and vomiting, stomatitis, diarrhea, and rash. Evidence for antitumor activity was seen in seven patients. Trimetrexate elimination from plasma could be represented as either a bi- or triexponential process. Terminal elimination half-lives were in the range of 5-14 h in patients represented by a triexponential model. Approximately 10-20% of the dose administered was excreted in urine over a 24-h period. The recommended starting dose for patients in Phase II trials using the d x5 i.v. schedule is 8.0 mg/m2/d repeated every 21 days. Dose escalations may be possible depending on the extent of prior therapy and individual tolerance of the drug.

Homoharringtonine-induced hyperglycemia.

Homoharringtonine (HHT) has been reported to induce hyperglycemia. This report describes a study conducted to characterize the effect of HHT on insulin production and action. Our data indicate that HHT-induced hyperglycemia results from the development of insulin resistance. A review of the literature suggests that patients receiving HHT continuous infusions of 5 mg/m2/d or greater and patients greater than 10 years of age may be at increased risk for the development of HHT-induced hyperglycemia. We recommend that patients with these risk factors, as well as diabetic patients and patients concurrently receiving asparaginase and/or prednisone, have their blood glucoses routinely monitored for hyperglycemia.