Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia.

PURPOSE: Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-beta-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease. DESIGN: Ara-C was given i.v. at a fixed dose of 1.5 gm/m(2)/d by continuous infusion for 4 days (patients ages <65 years at time of diagnosis) or 3 days (patients ages > or =65 years). Cloretazine was given i.v. over 15 to 60 minutes on day 2 at a starting dose of 200 mg/m(2), with escalation in 100 mg/m(2) increments in cohorts of three to six patients until a maximum tolerated dose was established. The DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) was measured at baseline. RESULTS: Forty patients, including 32 with acute myeloid leukemia, received 47 courses of treatment. Complete responses were seen at cloretazine dose levels of > or =400 mg/m(2) in 10 of 37 (27%) evaluable patients, and in this patient subset, AGT activity was significantly lower in patients that responded to treatment than in patients who did not (P < or = 0.027). Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen with 500 and 600 mg/m(2) of cloretazine combined with the 4-day ara-C schedule but not seen with the 3-day schedule. CONCLUSION: The recommended cloretazine dose schedule for future studies is 600 mg/m(2) combined with 1.5 gm/m(2)/d continuous infusion of ara-C for 3 days. The cloretazine and ara-C regimen has significant antileukemic activity. AGT activity may be a predictor of response to cloretazine.     

Fire exclusion and the changing landscape of Queensland’s Wet Tropics Bioregion 1. The extent and pattern of transition

The vegetation and geology of the Wet Tropics Bioregion of North Queensland, covering 1?998?150 ha, were mapped at a scale of 1:50?000. The resulting geographic information system (GIS) data base provided an unprecedented opportunity to examine vegetation condition across the entire bioregion. Mapping used colour aerial photography at 1:25?000, informed by ground truthing. Vegetation type, nature of the understory and ground cover, degree and type of disturbance, and the presence of secondary vegetation were described by a coding system, with codes marked directly on the aerial photos.

Analysis of these data has confirmed a picture, which emerged from ground truthing, of large areas of sclerophyll woodland and forest being invaded by a rainforest understory that prevents regeneration of the sclerophyll canopy. Fifty-three per cent of the native vegetation of the bioregion consists of non-rainforest vegetation types, dominated in both area and number by sclerophyll woodlands and forests. Seventeen per cent of the 735?713 ha of sclerophyll woodland and forest types were assessed as having suffered irreversible change. Between 25% and 79% of individual forest vegetation types were judged to have been affected by irreversible change. No climatic changes, or changes in the environment, apart from those related to changing fire regimes, were identified as causative factors. Changed fire regimes, predominantly fire exclusion, are considered to be the most likely cause.     

Combination Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Diabetic Kidney Disease

Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) have played a major role in slowing the progression of diabetic kidney disease, since they lower urine protein levels, lower blood pressure, and slow progression. Studies have suggested that the combination of ACE-I and ARB offered greater benefits for patients with diabetic kidney disease. In 2008, the large ONTARGET study reported no benefit with combination therapy, as compared with monotherapy. This study has changed practice patterns, but few patients in this study had diabetic kidney disease. In this review, the data in favor of the combination use of these agents in patients with diabetic kidney disease and data against the combination are reviewed. At this time, there is little support for using the combination in diabetic patients with no kidney disease or early stage diabetic kidney disease. But there are patients who may benefit from combination use.     

Diagnosis and Treatment of Retrorectal Abscess

Hemodynamic studies have shown that shock following myocardial infarction is caused primarily by sudden reduction in cardiac output to one-half of normal values, with unimportant changes in total blood volume. A high mortality accompanies this condition.

Treatment of heart block and ventricular tachycardia associated with shock can result in dramatic improvement. Morphine, oxygen and digitalis are considered routine treatment, and morphine alone may reverse hypotension without true cardiogenic shock. Although vasopressor agents may produce subjective improvement, in the author's experience they did not decrease the ultimate mortality.

Hypothermia and assisted circulation as therapeutic measures are currently in the experimental stage.     

Neonatal alcohol impairs the context preexposure facilitation effect in juvenile rats: Dose-response and post-training consolidation effects

Alcohol exposure on postnatal days (PND) 4-9 in the rat adversely affects hippocampal anatomy and function and impairs performance on a variety of hippocampus-dependent tasks. Exposure during this developmental window reveals a linear relationship between alcohol dose and spatial learning impairment in the context preexposure facilitation effect (CPFE), a hippocampus-dependent variant of contextual fear conditioning. The purpose of the current report was to examine the effect of a range of alcohol doses administered during a narrower window, PND7-9, than previously reported (Experiment 1) and to begin to determine which memory processes involved in this task are impaired by developmental alcohol exposure (Experiment 2). In Experiment 1, rats pups received a single day binge alcohol dose of either 2.75, 4.00, 5.25 g/kg/day or were sham-intubated (SI) from PND7-9. Conditioned freezing during the test day was evident in all dosing groups, except for Group 5.25 g, indicating no graded dose-related behavioral deficits with alcohol exposure limited to PND7-9. In Experiment 2, rat pups were exposed to the highest effective dose from Experiment 1 (5.25 g/kg/day) or were sham intubated over PND7-9. During training, rats remained in the conditioning context for 5-min following immediate shock delivery. During this test of post-shock freezing, both SI and alcohol-exposed rats given prior exposure to the conditioning context showed comparable freezing levels. Since alcohol-exposed rats showed normal post-shock freezing, deficits by these rats on the test day likely reflect a failure to consolidate or retrieve a context-shock association, rather than a deficit in hippocampal conjunctive processes (consolidation, pattern completion) that occur prior to shock on the training day. These findings illustrate the value of the CPFE for characterizing the separable memory processes that are impaired by neonatal alcohol exposure in this task.     

CD34+ human marrow cells that express low levels of Kit protein are enriched for long-term marrow-engrafting cells

Using in utero transplantation into fetal sheep, we examined the capability of human bone marrow CD34+ cells fractionated based on Kit protein expression to provide long-term in vivo engraftment. Twelve hundred to 5,000 CD34+ Kit-, CD34+ Kit(low), and CD34+ Kit(high) cells were injected into a total of 14 preimmune fetal sheep recipients using the amniotic bubble technique. Six fetuses were killed in utero 1.5 months after bone marrow cell transplantation. Two fetuses receiving CD34+ Kit(low) cells showed signs of engraftment according to analysis of CD45+ cells in their bone marrow cells and karyotype studies of the colonies grown in methylcellulose culture. In contrast, two fetuses receiving CD34+ Kit(high) cells and two fetuses receiving CD34+ Kit- cells failed to show evidence of significant engraftment. Two fetuses were absorbed. A total of six fetuses receiving different cell populations were allowed to proceed to term, and the newborn sheep were serially examined for the presence of chimerism. Again, only the two sheep receiving CD34+ Kit(low) cells exhibited signs of engraftment upon serial examination. Earlier in studies of murine hematopoiesis, we have shown stage-specific changes in Kit expression by the progenitors. The studies of human cells reported here are in agreement with observations in mice, and indicate that human hematopoietic stem cells are enriched in the Kit(low) population.