Motor activity of rats following intracerebral injections of drugs influencing GABA mechanisms

Summary Motor activity of rats was recorded following bilateral injections of GABA and the two GABA analogues gammahydroxybutyric acid (GHBA) and baclofen into the nucleus accumbens. GABA produced a shortlasting hypoactivity and this effect was potentiated by the GABA transaminase inhibitor aminooxyacetic acid (AOAA). More pronounced hypoactivities were caused by GHBA and baclofen. The hypoactivity was followed by hyperactivity after GHBA, baclofen and, to a small extent, after AOAA plus GABA. Systemic treatment with GHBA and GABA also suppressed motor activity and GHBA caused a subsequent hyperactivity. Small doses of GABA and particularly GHBA injected into the nucleus accumbens caused an increase in motor activity without the preceding decrease, especially when the rats were habituated to the environment. The effects appeared specific since no or only small changes in motor activity were induced by carnitine and betahydroxybutyric acid, structurally related to GABA and GHBA, respectively. Furthermore, the motor activity was stimulated by local treatment with the GABA receptor blocking agent picrotoxin, but not by strychnine or pentylenetetrazole. GHBA and GABA inhibited the apomorphine-induced activity of reserpine-treated rats indicating that these compounds stimulate GABA receptors beyond the dopamine synapses. The motor activity was depressed by GHBA and GABA given into the rostral and intermediate neostriatum and into the globus pallidus and, to a smaller extent, when given into the caudal neostriatum. The stimulatory effect of GHBA or picrotoxin was less, pronounced after local application to the globus pallidus or the neostriatum than when applied to the nucleus accumbens. The increased motor activity by GHBA, baclofen and GABA might be due to stimulation of GABA autoreceptors in the nucleus accumbens. The decreased motor activity might be evoked by stimulation of postsynaptic GABA receptors in the nucleus accumbens but a similar action in the corpus striatum might contribute.Part of the data was presented at the symposium on Interactions Among Putative Transmitters in the Brain held at the Mario Negri Institute, Milan, Italy on October 26–28, 1976     

Proliferation kinetics of the dermal infiltrate in cutaneous malignant lymphomas

Summary To obtain information about the role of local proliferation in the pathogenesis of dermal infiltrate in malignant cutaneous lymphomas, we determined the percentage of ³H-thymidine-labeled infiltrating cells (³H-index).A linear correlation was found between proliferative activity and clinical stage in mycosis fungoides, i.e., the ³H-index is moderately elevated in stage I and high in stage III.The ³H-index is within normal range in dermal infiltrate of Sézary syndrome, diffuse lymphocytic lymphoma, as well as in lymphocytoma benigna cutis.In parapsoriasis en plaques two groups can be distinguished: in the smallplaque variant (chronic superficial dermatitis) the ³H-index is low, whereas the large-plaque variant (prereticulotic poikiloderma) shows strong proliferative activity.Thus, determination of proliferative activity seems to give new insights into the pathogenesis of dermal infiltrate in cutaneous lymphomas.Zusammenfassung Um die Bedeutung der lokalen Zellproliferation im dermalen Infiltrat bei cutanen malignen Lymphomen zu untersuchen, bestimmten wir den Prozentsatz der ³H-Thymidin-markierten Infiltratzellen (³H-Index.Zwischen dem klinischen Stadium der Mycosis fungoides und der Proliferationsaktivität des dermalen Infiltrats besteht eine lineare Beziehung; im Stadium I ist die Proliferation niedrig, im Stadium III sehr hoch.Nicht erhöht ist der ³H-Index im dermalen Infiltrat beim Sézary-Syndrom, diffusen lymphocytischen Lymphom sowie bei Lymphocytoma benigna cutis.Bei der Parapsoriasis en plaques müssen zwei Formen unterschieden werden: bei der kleinfleckigen Form (chronic superficial dermatitis) ist der ³H-Index niedrig, während die großfleckige Form (Präretikulotisches Poikiloderm) eine starke Proliferationsaktivität aufweist.Die Untersuchung des Proliferationsverhaltens gibt neue Einblicke in die Pathogenese des dermalen Infiltrats cutaner Lymphome.     

Contribution of thallium-201-SPECT to the grading of tumorous alterations of the brain

Single photon emission computed tomography (SPECT) with thallium-201-chloride (²⁰¹TI) was used in 22 patients to assess the grade of malignancy of brain tumors.Low- and high-grade malignant gliomas could be well differentiated by calculating the Grade Index (GI), i.e., ²⁰¹TI uptake in the tumor area relative to a contralateral brain region. Low-grade gliomas (WHO-grade I–II) usually showed a GI of <1.5. Tumors classified histologically as high-grade malignant (WHO-grade III–IV) had GI values greater than 1.42 and a mean value of 1.89.Until labelled amino-acid tracers for gamma-cameras become commercially available, thallium-201 brain-SPECT can provide an independent and complementary method to CT/MRI for the differential diagnosis of grading of brain tumors. This simple technique can help to reduce sampling errors during needle biopsies of brain tumors, particularly of high-grade lesions incorrectly graded as low-grade tumors due to inadequate biopsy material. In addition, pre- and post-therapy studies can influence the strategy of therapy itself and allow an early detection of recurrences.     

Kluger's “Fixateur interne” for spinal instability

Kluger's Fixateur Interne proved to be an excellent tool not only in spinal trauma for repositioning of impacted fractures and transpedicular stabilization of the dorsal column but also in other forms of thoracic or lumbar instability.After spinal tumor excision from a dorsal approach and vertebral replacement with methylmethacrylate additional stability through dorsal fixation was achieved with this device.Spondylodiscitis, symptomatic spondylolisthesis, spinal instability from degenerative disc disease as well as nonunion following previous surgery could be cured using Kluger's internal fixation. Rare complications, i.e. from broken screws or rods (5%) caused no problems, but some patients required a second operation for readjustment of malpositioned screws which were causing pain or neurological deficit.     

Effects of molsidomine and dopamine infusion on the size of canine experimental myocardial infarct

Summary The effects of i.v. molsidomine and dopamine infusion on mean haemodynamic changes, myocardial oxygen consumption (pressure-rate-product), and ultimate infarct size were studied in pentobarbital-anaesthetized, open-chest dogs and compared to those occurring in dogs receiving saline infusion. Either agent was administered in a separate setting. Haemodynamic variables and oxygen consumption were determined during a 6-h period after ligation of the left anterior descending coronary artery and collected at 1-h intervals. Infarct size was determined by post-mortem nitroblue tetrazolium stain of intracellular lactic dehydrogenase enzymes. Coronary artery ligation during saline infusion (n=8) resulted in decreased blood pressure and cardiac output, whereas heart rate, systemic peripheral resistance, end-diastolic filling pressure and myocardial oxygen consumption increased. Infarct size amounted to 24.2±3.2% (i. e., 23.8±3.1 g) of left ventricular mass. Infusion of 1.4 g/kg/min molsidomine (n=8) produced significant fall of blood pressure, cardiac output, filling pressure and oxygen consumption while heart rate and peripheral resistance were unaffected. The infarct volume was reduced to 49% (P<0.01) of that observed in saline controls. The administration of 3 g/kg/min dopamine (n=8) elevated blood pressure and cardiac output initially with a subsequent reduction of either parameter. Arteriolar vascular resistance and oxygen consumption increased but filling pressure remained unchanged. Infarct size was not different from saline controls. Infusion of 6 g/kg/min dopamine, however, significantly increased blood pressure, heart rate, and peripheral resistance. Cardiac output and filling pressure fell and myocardial oxygen consumption rose. The histochemically measured final infarct was reduced to 13.5±1.8% of left ventricle (i. e., 16.2±2.2 g, P<0.05 vs saline control), but the hearts were edematous and haemorrhagic. Therapy with molsidomine appears promising in the treatment of clinical myocardial infarction with haemodynamic sequellae. The safe use of therapy with higher dopamine doses in patients with acute myocardial infarction, however, awaits further investigation.Part of the dopamine experiments were done at Bayer AG, Institut für Pharmakologie     

Catalysis of nitrosation in vitro and in vivo in rats by catechin and resorcinol and inhibition by chlorogenic acid

Measurements were made of the effects of phenolic compounds,some of which are present in the human diet, on the nitrosationof proline by nitrite to give N-nitrosoproline (NPRO). In vitro,resorcinol, catechin, p-nitrosophenol and phenol were catalystsand chlorogenic acid an inhibitor; guaiacol showed a marginalcatalytic effect. Both the catalytic and the inhibiting effectswere dependent on pH and on the concentration of phenolic compounds;catalysis by resorcinol and catechin was increased at optimalratios of [nitrite]: [phenolic compound]. Endogenous nitrosationwas examined in vivo by co-administration of nitrite, prolineand a phenolic compound to rats and by monitoring the amountof NPRO excreted in the urine. Under similar experimental conditions,the catalytic effects observed in vivo decreased in the sameorder as those observed in vitro: resorcinol > p-nitrosophenol> catechin > phenol guaiacol; chlorogenic acid acted asan inhibitor. Catalysis and inhibition of N-nitrosation in ratsin vivo appears to occur via mechanisms similar to those invitro, although the effects in vivo were smaller. The implicationsof our findings for the endogenous formation of N-nitroso compoundsand for variations in exposure due to different dietary constituentsin humans are discussed.     

An in vitro model for videoimaging of human bladder smooth muscle cell contractions

Knowledge regarding human bladder smooth muscle cell (SMC) physiology is very limited. Only a few specific medical therapies for bladder disorders have therefore been established. The objective of this study was to develop a model for videomicroscopy of bladder SMC contractions. Cells were isolated from human cystoprostatectomy specimens and cultured in a modified EMEM medium. These cells were identified as SMCs by means of immunohistochemistry. For videomicroscopy, the culture flasks were coated with a viscous agent to allow cell contraction. Contractions were visualized by means of a cell culture microscope with a time-lapse videosystem. For cholinergic stimulation of the cells, acetylcholine, in concentrations ranging from 100 μM to 10 mM, was applied. The percentage of contracting cells within the observation field was evaluated for quantitative analysis. In control experiments without contractile stimulant 6% of the cells were observed to contract. Stimulation with acetylcholine induced a significant dose-dependent increase to 47% in contracting cells. These results demonstrated that videomicroscopy is an appropriate tool to investigate the contraction mechanisms of bladder SMCs. This model offers the possibility of studying drug effects on the human detrusor in vitro. Received: 16 September 1999 / Accepted: 1 May 2000     

Association between the risk for lung adenocarcinoma and a (-4) G-to-A polymorphism in the XPA gene.

Polymorphisms of genes coding for DNA repair can affect lung cancer risk. A common single nucleotide (-4) G-to-A polymorphism was identified previously in the 5' untranslated region of the XPA gene. In a case-control study in European Caucasians, the influence of this polymorphism on primary lung cancer risk overall and according to histologic subtypes was investigated. Four hundred sixty-three lung cancer cases (including 204 adenocarcinoma and 212 squamous cell carcinoma) and 460 tumor-free hospital controls were investigated using PCR amplification and melting point analysis of sequence-specific hybridization probes. Odds ratios (OR) were calculated by multiple logistic regression analysis adjusting for age, gender, smoking habits, and occupational exposure and showed a slightly enhanced risk for all lung cancer cases as well as for squamous cell carcinoma and adenocarcinoma cases. Gene-environment interactions were analyzed with respect to smoking and occupational exposure. A nearly 3-fold increased risk for adenocarcinoma associated with the XPA AA genotype was observed for occupationally exposed individuals (OR, 2.95; 95% confidence interval, 1.42-6.14) and for heavy smokers (OR, 2.52; 95% confidence interval, 1.17-5.42). No genotype-dependent increase in OR was found for nonexposed individuals or those smoking <20 pack-years. The significant effect of the XPA polymorphism in heavy smokers and occupationally exposed individuals suggests an important gene-environment interaction for the XPA gene. The underlying mechanisms as to why AA homozygotes are predisposed to lung adenocarcinoma and which specific carcinogens are involved remains to be determined.     

Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

PURPOSE: To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial presentation. PATIENTS AND METHODS: Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions. RESULTS: With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate [RHR] = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes. CONCLUSION: The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.