Phase I study of VRCTC-310, a purified phospholipase A2 purified from snake venom, in patients with refractory cancer: safety and pharmacokinetic data

A phase I study was performed to evaluate the maximum tolerated dose (MTD), safety profile and pharmacokinetic data with VRCTC-310, a natural product derived from purified snake venom fractions, with phospholipase A2 activity and inhibitory effects against human and murine tumor cell lines. Fifteen patients with refractory malignancies were entered after providing written informed consent. VRCTC-310 was administered as an intramuscular injection daily for 30 consecutive days. Doses were escalated from 0.0025 to 0.023 mg/kg. Toxicities included local pain at the injection site, eosinophilia, reversible diplopia and palpebral ptosis. Dose escalation was stopped at 0.023 mg/kg, when two patients had developed anaphylactoid reactions. Both cases had high VRCTC-310-specific IgG by EIA. MTD was 0.017 mg/kg and the recommended dose for phase II studies is 0.017 mg/kg. Stabilization was found in six patients.     

Characterization of recombinant E. coli ATCC 11303 (pLOI 297) in the conversion of cellulose and xylose to ethanol

This work describes the characterization of recombinant Escherichia coli ATCC 11303 (pLOI 297) in the production of ethanol from cellulose and xylose. We have examined the fermentation of glucose and xylose, both individually and in mixtures, and the selectivity of ethanol production under various conditions of operation. Xylose metabolism was strongly inhibited by the presence of glucose. Ethanol was a strong inhibitor of both glucose and xylose fermentations; the maximum ethanol levels achieved at 37 degrees C and 42 degrees C were about 50 g/l and 25 g/l respectively. Simultaneous saccharification and fermentation of cellulose with recombinant E. coli and exogenous cellulose showed a high ethanol yield (84% of theoretical) in the hydrolysis regime of pH 5.0 and 37 degrees C. The selectivity of organic acid formation relative to that of ethanol increased at extreme levels of initial glucose concentration; production of succinic and acetic acids increased at low levels of glucose (< 1 g/l), and lactic acid production increased when initial glucose was higher than 100 g/l.     

Expanded phase II trial of paclitaxel in metastatic breast cancer: a Southwest Oncology Group study

In digital image processing, the homomorphic filtering approach is derived from an illumination-reflectance model of the image. Homomorphic filtering can perform simultaneous dynamic range compression and contrast enhancement. Crucial for the success of the homomorphic approach is the selection of an appropriate frequency-domain filter function in order to modify the illumination and reflectance components of an image differently. The author found Butterworth type highpass equations far superior to other frequency-domain filter functions, including Gaussian equations, making the Butterworth highpass suitable for use with the homomorphic filtering approach. The program was written in Microsoft (MS) Visual C++ (filter) as well as MS Visual Basic (user interface) to run as a module under the image processing software package Image-Pro Plus.     

Whole body bone resorption in the growing pig

Our knowledge of total body bone resorption during growth is limited. The primary purpose of this study was to determine if a commercially available bone resorption assay, developed for measuring human bone resorption, could be used to measure whole body bone resorption in young, growing pigs. A secondary purpose was to evaluate if this method could detect changes in bone resorption in response to certain dental appliances which have been shown to change mandibular and maxillary growth. Five growing 4-month-old male Hanford minipigs (Sus scrofa) were housed in metabolic cages for 24 h, every other day, over a period of 1 month. Three of the animals were fitted with a mandibular protrusive orthodontic appliance. Total 24 h urines were collected in which the concentration of creatinine and collagen type I N-telopeptide crosslinks (NTx, a marker of bone resorption) were measured. The NTx immunoassay was originally developed for the analysis of human urine. Pig bone was powdered, defatted, and decalcified, and the resulting powder digested with bacterial collagenase. The digest was screened for NTx content, in the same fashion as the pig urines. Bone extract and pig urines were cross-calibrated to a standard of adolescent human urine. This allowed calculation of the daily quantity of pig bone resorbed. Daily metabolite excretion was quite variable in these growing animals; for NTx the CV was 31%, for creatinine the CV was 25%. The mean daily quantities of bone resorption ranged between 26 and 46 grams of bone which amounted to 1.2-1.7% of estimated total skeletal mass. The protrusive appliances increased bone resorption significantly during the first two weeks of the trial. In conclusion: the NTx assay can be used to measure bone resorption in pigs; the assay is sensitive enough to indicate changes in bone resorption, such as those caused by an orthodontic mandibular protrusive appliance. During growth, bone resorption varies greatly from day to day. On average, every 24 h, 1.4% of the skeletal mass is resorbed.     

Improvement of the exercise test after therapy in thyrotoxic periodic paralysis

The diagnosis of periodic paralysis (PP) can be aided by demonstrating a decrease in compound motor action potential (CMAP) amplitude after several minutes of exercise. We report a case of secondary hypokalemic PP due to thyrotoxicosis in which the decrease in the CMAP amplitude after exercise dramatically improved after treatment, when a euthyroid state was achieved. The exercise test is a useful electrophysiologic means of monitoring the neuromuscular status of patients with thyrotoxic periodic paralysis prior to, and after treatment of the thyrotoxicosis.     

Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.     

Family functioning and mental illness: a comparison of psychiatric and nonclinical families

The primary objective of the present investigation was to examine adaptive functioning in the families of patients with a wide range of psychiatric disorders. Seven dimensions of family functioning, as measured by the Family Assessment Device (FAD), were compared across families of patients with a schizophrenia spectrum disorder (n = 61), bipolar disorder (n = 60), major depression (n = 111), anxiety disorder (n = 15), eating disorder (n = 26), substance abuse disorder (n = 48), and adjustment disorder (n = 46). Families in each psychiatric group were also compared to a control group of nonclinical families (N = 353). Results indicated that regardless of specific diagnosis, having a family member in an acute phase of a psychiatric illness was a risk factor for poor family functioning compared to the functioning of control families. However, with few exceptions, the type of the patient's psychiatric illness did not predict significant differences in family functioning. Thus, having a family member with a psychiatric illness is a general stressor for families, and family interventions should be considered for most patients who require a psychiatric hospitalization for either the onset of, or an acute exacerbation of, any psychiatric disorder.     

Developmental changes in neuronal responsiveness to the CNS myelin-associated neurite growth inhibitor NI-35/250

The extent of fibre regeneration in the adult injured vertebrate nervous system appears to be primarily determined by the local environment. Thus, the failure of axon regrowth in the central nervous system (CNS) is crucially influenced by the presence of the myelin-associated neurite growth inhibitor NI-35/250 and possibly also by molecules such as the myelin-associated glycoprotein and the proteoglycans. Developmental time course studies have shown that the capacity for regeneration declines sharply with the appearance of mature oligodendrocytes and myelin, which indicates a role of NI-35/250 in restricting CNS regeneration and plasticity. However, recent in vitro and in vivo studies showed that embryonic neurons are capable of extending fibres on and in adult CNS tissue apparently unaffected by myelinated areas. A possible explanation is that very immature neurons have yet to express the appropriate receptors and response mechanisms for factors that normally induce growth inhibition at a later stage of development. Here we report that embryonic rat dorsal root ganglion and chick retinal ganglion cells display different sensitivity to bovine NI-35/250 compared with mature neurons. In older neurons NI-35/250 could evoke long-lasting collapse responses accompanied by a large increase in the intracellular calcium level, persisting for several minutes. In contrast, their embryonic counterparts collapsed only transiently when exposed to NI-35/250, and increases in intracellular calcium concentration were small and transient. Calcium influx induced experimentally by the calcium ionophore A23187 revealed that it was not the maximal size of the calcium increase but rather the duration of elevated calcium concentration that was the most important determinant for subsequent morphological alterations of the growth cone. Our data further suggest that developing neurons acquire their complete sensitivity for NI-35/250 around the time of myelination.     

Maternal attachment status, psychosocial stressors and problem behaviour: follow-up after parent training courses for conduct disorder

37 Mothers of children with conduct disorder who had received Parent Management Training (PMT) were interviewed using the Adult Attachment Interview, 13-43 months after treatment. Child behaviour levels at follow-up were strongly associated with the scores at referral in the unresolved attachment group, but not in the resolved group. This was reflected in a statistical interaction between referral behaviour score and resolved/unresolved attachment status in a regression model. This model, which also included a strong independent contribution from a composite psychological stress index, explained 66% of the variance in follow-up behaviour scores. The implications of these results for predicting the outcome of PMT are discussed.