Ischemia and loss of ATP in tumours following treatment with focused high energy shock waves.

High energy shock waves (HESW) have been reported to be cytotoxic to tumour cells in vitro and in vivo. For that reason they are evaluated as a new modality for cancer treatment. In the present study we have quantified the effect of treatment with multifocal HESW on tumour blood flow and energy status. Blood flow and adenosine triphosphate (ATP) concentration were investigated simultaneously in tumour and adjacent tissue of six treated and six untreated amelanotic hamster melanomas (A-Mel-3) at 3, 12 or 24 h after multifocal application of HESW. 14C-iodoantipyrine autoradiography for blood flow measurements and quantitative ATP imaging bioluminescence were employed. Following treatment, tumour blood flow and ATP concentration were significantly reduced, as compared to control, over the entire period of observation. Three hours after HESW, blood flow and ATP concentration were at the background level. In adjacent tissue, blood flow and ATP concentration were distinctly diminished. We therefore conclude that multifocal HESW induce a breakdown of tumour-, and adjacent tissue perfusion which is accompanied by a significant decrease of intracellular ATP concentration.     

Morphological and morphometric studies of the dysmyelinating mutant, the Long Evans shaker rat

The Long Evans shaker (les) rat is a recently identified CNS myelin mutant with an autosomal recessive mode of inheritance. Although scattered myelin sheaths are present in some areas of the CNS, most notably the ventral spinal cord in the young neonatal rat, this myelin is gradually lost, and 8-12 weeks little myelin is present throughout the CNS. Despite this severe myelin deficiency, some mutants may live beyond one year of age. Rare, thin myelin sheaths that are present early in development lack myelin basic protein (MBP) and on ultrastructural examination are poorly compacted and lack a major dense line. Many oligodendrocytes develop an accumulation of vesicles and membranous bodies, but no abnormal cell death is observed. In the optic nerve, cell kinetic studies show an increase in proliferation at early time points in les, while total glial cell counts are also increased in les from 2 months of age. In situ hybridization studies demonstrate that the numbers of mature oligodendrocytes are similar to controls early in life and increase with time compared to controls. There is both a progressive astrocyte hypertrophy and microgliosis. While les has a mutation in the myelin basic protein (mbp) gene, it is dissimilar in both genotype and phenotype to the previously described mbp mouse mutants, shiverer (shi) and shiverermld. Unlike shi and its allele, where myelin increases with time and oligodendrocytes become ultrastructurally normal, les oligodendrocytes are permanently disabled, continue to demonstrate cytoplasmic abnormalities, and fail to produce myelin beyond the first weeks of life.     

Topical application of a first porphycene dye for photodynamic therapy – penetration studies in human perilesional skin and basal cell carcinoma

Photodynamic therapy (PDT) in dermatology has been proven to be a successful noninvasive therapeutic modality for treating skin cancer. To facilitate its clinical introduction, the development of topical photosensitizers is necessary to avoid generalized, cutaneous photosensitivity. Therefore the penetration of synthetic chemically pure 9-acetoxy-2,7,12,17-tetrakis-(β-methoxyethyl)-porphycene (ATMPn) into human skin was studied. Single specimens of freshly excised perilesional skin ( n = 70) and basal cell carcinomas ( n = 28) were evaluated after topical application of ethanolic ATMPn solutions (0.1% and 0.05%) for various times (2, 6, 16, 20 h). The penetration depth of ATMPn, recognized as red fluorescence in cryostat sections, was determined qualitatively by fluorescence imaging using a system of scoring related to the morphological structure of human skin (0 no fluorescence, 5 fluorescence deeper than basement membrane). Perilesional skin incubated for 2 or 6 h revealed fluorescence restricted to the upper parts of the epidermis, while after 16 or 20 h of incubation fluorescence was detected down to the basement membrane resulting in a significantly higher score (mean sum of scores : 2 h 2.6 ± 0.4; 6 h 3.2 ± 0.1; 16 h 3.8 ± 0.1; 20 h 3.6 ± 0.1). Quantitative evaluation by digital image analysis confirmed the qualitative results. Fluorescence was limited to the epidermis and the fluorescence intensity of the epidermis was higher after 16 h (4.9% of the fluorescence standard) than after 6 h (4.1%) incubation. Basal cell carcinomas showed fluorescence in the deep dermis as early as after 6 h incubation, but restricted to tumour cell nests. These results suggest that penetration of ATMPn into tumour tissue after topical application might be sufficient for topical PDT and that poor penetration into surrounding tissue might prevent scar formation following irradiation for PDT. The penetration characteristics of ATMPn now have to be proven in an in vivo setting. Received: 30 May 1996     

Effect of Stereotaxic Intrastriatal Cografts of Autologous Adrenal Medulla and Peripheral Nerve in Parkinson''s Disease: Two-Year Follow-up Study

Studies in nonhuman primates with experimental parkinsonism have shown that intrastriatal cografts of autologous adrenal medulla and peripheral nerve yield greater behavioral improvement and graft survival than do adrenal medulla grafts alone. To test these observations, five patients with advanced Parkinson's disease were selected to receive unilateral intrastriatal adrenal medulla-intercostal nerve cografts. They were evaluated using the Core Assessment Program for Intracerebral Transplantation (CAPIT) protocol. Three of these patients also underwent quantitative motor testing for the measurement of upper limb bradykinesia (movement time; MT). Following right flank adrenalectomy, cografts consisting of small fragments of adrenal medullary tissue and minced intercostal nerve were stereotaxically implanted into three targets in the right striatum using computerized tomography guidance. Surgery was uneventful and postoperative magnetic resonance imaging revealed accurate placement of the grafts. No morbidity was encountered. Results of 24 months of clinical and quantitative motor assessments postoperatively are reported. Total UPDRS motor scores in the “off” state improved from a mean preoperative score of 39.5 to 32.1 at 3, 29.7 at 6, 27.6 at 9, 28.5 at 12, 31.4 at 18, and 26.5 at 24 months after surgery. Total timed motor test scores during the “off” state improved 17.9% at 6, 23.3% at 9, 18.2% at 12, 38.2% at 18, and 34.9% at 24 months postoperatively compared to baseline. Movement time showed statistically significant improvement (repeated measures ANOVA,P < 0.05) in the left arm (contralateral to surgery) in all three patients tested. These results indicate that stereotaxic intrastriatal implantation of autologous adrenal medulla-peripheral nerve cografts can be performed safely and clinical improvement from this procedure is sustained for a period of 24 months. The clinical improvement was paralleled by improvement in objective, quantitative motor testing.     

Laser induced removal of meniscus cartilage and tendines

This study examines the potential of Nd-YAG lasers with the wavelength 1064 nm or 1320 nm and an Excimer XeCl laser for endoscopic removal of meniscus cartilage and tendon tissue. In vitro irradiation of freshly isolated bovine menisci and tendines with laser light, induced a tissue vaporization and tissue ablation with a highly significant relation to the applied laser energy density. In contrast to the treatment of tissue with the Excimer laser the use of the Nd-YAG laser with both wavelengths provoked carbonization of the lesion surface. Thermic induced changes of tissue integrity as examined by histology and scanning-electron-microscopy were for the Nd-YAG laser with wavelength 1320 nm>Nd-YAG laser with wavelength 1064 nm> Excimer XeCl laser. Due to the smaller thermic induced side effects and the smoother tissue surface after irradiation the pulsed Excimer XeCl laser is favoured for cutting and ablation in meniscus and tendon surgery.     

Cholinergic REM sleep induction in atypical depression

The arecoline REM induction test, a measurement of central cholinergic sensitivity, was performed in 10 patients with atypical depression. Arecoline induced REM sleep significantly more rapidly than placebo. Atypical depressives without evidence of anxiety, in particular those without panic attacks, had a more rapid REM induction response to arecoline than atypicals with anxiety symptoms. We compared our atypical depressives with normal controls and affectively ill patients studied in other laboratories. The rapid REM induction response observed in atypical depressives without anxiety was comparable to that seen in endogenous depressives and euthymic bipolars. Previous studies have demonstrated the presence of cholinergic supersensitivity in the latter two groups of patients. Our results suggest that atypical depressives may be distinguished in their response to arecoline based on their anxiety history, and that cholinergic supersensitivity is present in atypical depressives without anxiety. Additional studies with larger samples and simultaneously studied control groups are necessary to test these preliminary findings.     

Evaluation of a modified inverted walking stick as a treatment for parkinsonian freezing episodes

We evaluated a modified inverted walking stick [visual cue (VC) stick] in Parkinson's disease patients with freezing episodes. Patients underwent baseline trials on a 60-ft track with four walking conditions: unassisted, with a straight walking stick, with the VC stick, and on the track with parallel lines spaced every 12 in. Patients completed three trials of each condition in a randomized order, with total course time and number of freezes recorded. Patients were given the VC stick to use at home until subjective maximum functional benefit was obtained and were then brought back for a follow-up objective evaluation. Eight patients completed the study. The straight stick and VC stick worsened patient performance as a group, while the parallel lines significantly improved group performance. However, two of the eight patients showed benefit from the VC stick. Improvement with parallel lines did not predict improvement with the VC stick. On follow-up trials, the two who initially showed improvement with the VC stick continued to show improvement, while none of the other patients showed additional benefit from a learning effect. We conclude that the VC stick will help a small subpopulation of Parkinson's disease patients with freezing, and this subpopulation can be identified with the initial office visit trial.     

Cochlioquinone A, a nematocidal agent which competes for specific [3H]ivermectin binding sites

Cochlioquinone A, isolated from the fungus Helminthosporium sativum, was found to have nematocidal activity. Cochlioquinone A is a competitive inhibitor of specific [3H]ivermectin binding suggesting that cochlioquinone A and ivermectin interact with the same membrane receptor.     

The pharmacology of the lipoxygenase inhibitors oxphaman (1-(2,5-dihydroxybenzylidene)aminoadamantane) and oxphalin (1-(3,4-dihydroxybenzylidene)-2,4,6-trimethylaniline

Oxphaman and particularly oxphalin, among other phenolic azomethines, have been proven as strong inhibitors of lipoxygenases (LOX) from reticulocytes, soybean, thrombocytes as well as of quasi-LOX (hemoglobin) with IC50 values which correspond with those of known LOX inhibitors. The 5-LOX is likewise strongly, the cyclooxygenase of sheep seminal vesicles only weakly inhibited. Nevertheless, antiinflammatory effectivity was found in some carrageenin-induced inflammatory models of the rat as well as in the arachidonic acid- and croton oil-induced ear oedema of the mouse. Adjuvant arthritis, experimental pain, skin permeability and allergy models (anaphylactic paw oedema, cutaneous anaphylaxis, asthma, picryl chloride ear oedema) were not, only weakly or irregularly influenced. In the guinea pig ileum a certain antihistaminic, anticholinergic and leukotriene antagonistic activity was found. An inflammation-induced vasodepression (anaphylactic shock, dextran paw oedema. UV irradiation) was dose-dependently prevented or even reversed, obviously on the basis of oxygen radical scavenging.