VRCTC-310--a novel compound of purified animal toxins separates antitumor efficacy from neurotoxicity

Two purified animal venom toxins, crotoxin and cardiotoxin, have been combined to produce a unique natural product (VRCTC-310) currently under investigation as an antitumor agent by the National Cancer Institute. In vitro, it has demonstrated cytotoxic disease specificity and a unique mechanism of action when submitted to COMPARE analysis. In vivo, tolerance was developed to the neurotoxic properties of crotoxin which allowed comparison of several schedules of fixed and escalating daily i.m. doses to mice bearing s.c. Lewis Lung carcinoma. An 83% inhibition of tumor growth was achieved using an escalating dose schedule starting at 1.8 mg/kg and reaching 6.3 mg/kg/day on day 20. Although some irritation around the sites of i.m. injection was noted, animal weight loss was negligible and there were no other signs of adverse toxicity. This natural product represents a new, membrane interactive anticancer agent which produces a unique spectrum of cytotoxicity in vitro and which has demonstrated interesting in vivo antitumor efficacy.     

Successful surgical repair for a patient with atrial septal defect and severe pulmonary hypertension--its surgical indication and prostaglandin E1 use for postoperative pulmonary hypertensive crisis

A 45-year-old woman with atrial septal defect and pulmonary hypertension was admitted for surgical repair. Cardiac catheterization data revealed pulmonary to systemic flow ratio (Qp/Qs) of 1.81, pulmonary artery pressure (PAP) of 82/30 mmHg and pulmonary vascular resistance (PVR) of 10.8 unit. Open lung biopsy was added to evaluate pulmonary vascular obstructive disease (PVOD) which was shown Heath-Edwards grade 3 PVOD. Following closure of the defect, PAP (systolic) exceeded momentarily systemic level after cardiopulmonary bypass. Prostaglandin E1 drip was remarkably effective to bring down PAP during early postoperative period. Although PAP has not been shown significant decrease on catheterization of one year after surgery, great symptomatic improvement has been achieved.     

Granulation tissue polyposis associated with carcinoid tumours of the small intestine

We report two patients with ileal carcinoid tumours which were associated with polyps due to mucosal granulation tissue proliferation. In both cases the tumours had extensively infiltrated the small bowel wall and mesentery, and one had hepatic metastases. The mucosal surface of each specimen showed numerous, pale brown, sessile polyps which were restricted to the intestinal segment involved by carcinoid tumour, although not always closely related to neoplastic cells. The polyps were formed by the proliferation of capillaries, smooth muscle cells and myofibroblasts as demonstrated by immunohistochemistry and electronmicroscopy.     

Robust stabilization for uncertain time-delay systems containingsaturating actuators

A class of uncertain time-delay systems containing a saturating actuator is considered. These systems are characterized by delayed state equations (including a saturating actuator) with norm-bounded parameter uncertainty (possibly time varying) in the state and input matrices. The delay is assumed to be constant bounded but unknown. Using a Razumikhin approach for the stability of functional differential equations, upper bounds on the time delay are given such that the considered uncertain system is robustly stabilizable, in the case of constrained input, via memoryless state feedback control laws. These bounds are given in terms of solutions of appropriate finite dimensional Riccati equations     

Innervation of VIP-immunoreactive neurons by the ventroposteromedial thalamic nucleus in the barrel cortex of the rat

We investigated the synaptic terminals of fibers originating in the ventroposteromedial thalamic nucleus (VPM) and projecting to the main input layers (IV/III) of the rat posteromedial barrel subfield. It was our aim to determine whether or not the subpopulation of vasoactive intestinal polypeptide (VIP)-immunoreactive neurons in these layers are directly innervated by the sensory thalamus. Anterograde tracing with Phaseolus vulgaris leucoagglutinin (PHA-L) and immunohistochemistry for VIP were combined for correlated light and electron microscopic examination. Columns of cortical tissue were well defined by barrel-like patches of PHA-L-labeled fibers and boutons in layers IV and III. Within these columns VIP-immunoreactive perikarya were located mainly in supragranular layers. Marked perikarya were also seen in infragranular layers, but their immunoreactivity was often weaker. Granular layer IV, which is the main terminal field for thalamic fibers, contained fewer VIP neurons than supragranular layers. In the light microscope, however, PHA-L-labeled fibers appeared to contact the somata or proximal dendrites of 60-86% of the layer IV VIP neurons . By contrast, only 18-35% of the VIP neurons in the supragranular layers, which receive a moderately dense projection from the VPM, appeared to be contacted. PHA-L-labeled boutons were seen close to 13-25% of infragranular VIP-positive cells. Electron microscopy showed that thalamic fibers formed at most four asymmetric synapses on a single layer IV, VIP-positive neuron. Although the proportion of VIP-positive neurons with labeled synapses was lower in supragranular layers, most of them shared multiple asymmetric synapses with labeled thalamic fibers. Up to six labeled synapses were seen on individual VIP neurons in layer III. We conclude that subpopulations of VIP-immunoreactive neurons, located in layers IV, III, and II are directly innervated by the VPM. These neurons may be involved in the initial stages of cortical processing of sensory information from the large, mystacial vibrissae. Since VIP is known to be colocalized with the inhibitory transmitter GABA, it is likely that VIP neurons participate in the shaping of the receptive fields in the barrel cortex.     

Differential therapy of cerebral arteriovenous malformations. An analysis with reference to personal microsurgery experiences

A total of 126 patients (63 female, 63 male) underwent microsurgical removal of their cerebral arteriovenous malformations (AVMs) by the same surgeon. The mean age at surgery was 34.7 (6-72) years. The symptoms were intracerebral hemorrhage (37.3%), seizure disorder (34.9%) or focal neurological deficits and minor symptoms. According to the Spetzler/Martin scale, 20.6% of the AVMs were grade I, 28.6% grade II, 32.5% grade III, 14.3% grade IV and 4% grade V. In all, 78 AVMs (61.9%) were located in functionally important brain regions. The series was split into three different groups: small AVMs under 3 cm in diameter (n = 62/49.2%), medium-sized AVMs (n = 58/46%) and large AVMs (n = 6/4.8%). Seventeen patients had preoperative embolization of their AVM. All patients had postoperative angiographic control and 3- and 6-month follow-up. One patient died (0.8%), and another one (0.8%), in whom the AVM was incompletely resected, suffered a secondary hemorrhage. Seventeen (27.4%) of the patients with small AVMs developed transient neurological worsening post-operatively, which remained permanently significant in 3.2%. The respective numbers for the patients with medium-sized AVMs were 48.3% and 10.3% and for the large AVMs 83.3% and 33.3%. The results of microsurgical removal of cerebral AVMs can still be considered superior to the results of stereotactic radiosurgical treatment available from the literature-even for small AVMs. This is due to immediate exclusion of the AVM under direct local control of the angioarchitecture and thereby a reduced risk of secondary hemorrhaging and a decreasing morbidity rate with increasing time after the operation. Radiosurgical treatment requires a 2-year latency period for obliteration and carries a mortality rate of up to 12.5% and a rate of unexpected side effects of up to 20%. This treatment should be reserved for small, deep, surgically inaccessible AVMs or used as part of a multimodality treatment regimen consisting of partial embolization, partial excision and consecutive radiation of the residual nidus in initially very large AVMs. Embolization therapy-such as radiosurgery-carries a significant risk of morbidity (8%) and a mortality rate of up to 6%. It should only be considered for AVMs that are expected to be fully obliterated afterwards, or for primary inoperable AVMs that are to be changed into operable ones by embolization. Size reduction of otherwise operable AVMs does not justify the additional risk of embolization. Close collaboration of the specialties involved is desirable.     

Characterization of differing effects caused by homeopathically prepared and conventional dilutions using cytochrome P450 2E1 and other enzymes as detection systems

Determination of cytochrome P450 2E1 activity was carried out via hydroxylation of the synthetic substrate p-nitrophenol to p-nitrocatechol. Crude microsomal preparation isolated from rat liver served as source for cytochrome P450 2E1. Under assay conditions guaranteeing a linear course of the reaction the cytochrome P450 2E1 was stimulated in the presence of a 10(-6) dilution of As2O3 corresponding to 0.915 microM final concentration compared with control. All other concentrations of As2O3 used inhibited the enzyme activity more or less drastically. Furthermore, we used this enzyme system to study the influence of arsenicum album (As2O3) and potassium cyanatum (KCN) in homeopathically prepared (i.e., by consecutive 1:10 steps) and conventional dilutions. We found significant differences between the effects caused by homeopathic potencies (D) and equally concentrated dilutions on catalytic activity of cytochrome P450 2E1. Such differing effects were observed in the case of arsenicum album (As2O3) between D4/10(-4) and D6/10(-6) and in the case of potassium cyanatum (KCN) between D6/10(-6) and D12/10(-12). When we used glutathione-S-transferases and uricase we also found different effects mediated by potencies and conventional dilutions. The results obtained suggest that these three enzyme systems are appropriate detection systems to hunt out differing effects of differently prepared dilutions of specific test substances.     

Expert statement and assessment of medical impairment in work-related pulmonary disease

The Norwegian Societies of Thoracic Medicine and Occupational Medicine established a working group to standardise diagnostic procedures and evaluation of work-related respiratory disorders. In cases of suspected work-related diseases the physician may be asked by the National Insurance Administration or an insurance company to make a statement which will be one of the documents used to decide the patient's right to compensation benefit. We discuss the role of the physician as an independent expert. This is different from his role as clinician. The statement should include a balanced presentation of information from different sources, including health and occupational history, and the employer's information about the work environment (quantitative and qualitative exposure data). The statement must also include the results of a clinical examination and an assessment of functional status based on objective tests. The paper contains recommendations for evaluation of permanent impairment in light of the present Norwegian laws and regulations.