Autosomal dominant striatonigral degeneration. A clinical, pathologic, and biochemical study of a new genetic disorder

An autosomal dominant striatonigral degeneration is present in a family of Portuguese ancestry numbering in excess of 329 persons in eight generations. The illness begins in the second, third, or fourth decade, and progresses for about 15 years with parkinsonian rigidity, spasticity, spastic dysarthria, and abnormalities of eye movement. Neuropathologic findings are severe neuronal loss and astrocytic gliosis in the corpus striatum and substantia nigra, with a moderate neuronal loss in the dentate nucleus of the cerebellum and nucleus ruber of the midbrain. This is a new genetic entity, distinct from other autosomal dominant neurologic disorders such as nigrospinodentatal degeneration, olivopontocerebellar degeneration, dystonia musculorum deformans, Machado's disease, and Huntington's disease.     

Effects of delta9-tetrahydrocannabinol on neurotransmitter accumulation and release mechanisms in rat forebrain synaptosomes

Previous studies involving the end-to-end fusion of the forelimbs of the adult newt have demonstrated that new limbs can regenerate from the transected ends of proximo-distally reversed limb segments. The limb regeneration could only have been initiated by nerve fibers of contralateral origin. The purpose of the present study is to describe histologically the manner in which nerve fibers of contralateral origin regenerate through the junction of fused limbs into the opposite limb. The first sign of nerve regeneration into the opposite limb was observed at eight days post fusion. The nerves crossed over into the opposite, originally denervated limb in a highly dispersed manner. These nerve fibers eventually aggregated, however, either under the skin or within persisting nerve trunks. By 19 days post fusion the nerve fibers had reached the elbow region of the originally denervated limb and by 25 days they were seen at the most proximal extent of the limb. The diameters of the axons seemed smaller than the diameters of regenerating axons observed in non-fused newt forelimbs.     

Detection of the sites of alkylation in DNA and polynucleotides by laser Raman spectroscopy

A laser Raman study of the alkylation of calf thymus DNA, poly(dG)-poly(dC) and poly(dA)-(dT) has been made using two water soluble alkylating agents: an antitumor drug, the difunctional methyl nitrogen mustard (HN2), which froms interstrand cross-links, and the dimethyl nitrogen half mustard (HN1). When an excess of the alkylating agent was used, the observed Raman frequencies due to the guanine ring modes in DNA and poly(dG)-poly(dC) changed virtually quantitatively to those of 7-methylguanosine (7-Me-Guo) showing that essentially all of the guanine bases were alkylated in the N-7 position. Furthermore, this alkylated DNA formed a stable double helical complex at neutral pH in which the alkylated guanine residues are in the keto form. No changes in the Raman bands of any of the other bases were observed in alkylated DNA. The DNA double helix, completely alkylated in at the N-7 position of guanine, melts about 35 degrees C below that of the native DNA. Upon melting, the alkylated guanine changes from the keto to the zwitterionic form.     

Common and specific determinants for fibroblast growth factors in the ectodomain of the receptor kinase complex

The assembly and activation of oligomeric complexes of FGF, the transmembrane receptor kinase (FGFR), and heparan sulfate transmit intracellular signals regulating growth and function of cells. An understanding of the structural relationships between the three subunits and their redundancy and specificity is essential for understanding the ubiquitous FGF signaling system in health and disease. Previously, we reported that a primary heparin or heparan sulfate binding site resides in a distinct sequence in immunoglobulin (Ig)-like module II of the three modules of FGFR. Here we report that in the absence of flanking sequences, isolated Ig module II of FGFR1 supports the binding of FGF-1, FGF-2, and FGF-7 in respective order of affinity. None of the three FGFs detectably bind Ig module I or the IIIb and IIIc splice variants of Ig module III in the absence of flanking sequences. Ig module I and the C-terminus of Ig module III are dispensable for high-affinity binding of FGF-1, FGF-2, and FGF-7. Alterations in highly conserved Ig module II in the heparin binding domain and substitution of individual sequence domains spanning the entire sequence of Ig module II with those from Ig module I obliterated FGF binding. Addition of a specific number of FGFR sequences to the C-terminus of Ig module II resulted in a gain in affinity for FGF-7. Several site-specific alterations in the C-terminus of full-length FGFR1IIIc, an isoform that otherwise absolutely rejects FGF-7, resulted in gain of FGF-7 binding. These results suggest that a complex of Ig module II and heparan sulfate is the base common active core of the FGFR ectodomain and that flanking structural domains modify FGF affinity and determine specificity.     

Cathepsin-D in primary breast cancer: prognostic evaluation involving 2810 patients

There is controversy regarding the prognostic value of cathepsin-D in primary breast cancer. An increased level of cathepsin-D in tumour extracts has been found to be associated with a poor relapse-free and overall survival. Studies performed with immunohistochemistry or Western blotting have produced diverse results. We have analysed 2810 cytosolic extracts obtained from human primary breast tumours for cathepsin-D expression, and have correlated their levels with prognosis. The median follow-up of the patients still alive was 88 months. Patients with high cathepsin-D levels had a significantly worse relapse-free and overall survival, also in multivariate analysis (P < 0.0001). Adjuvant therapy which was associated with an improved prognosis in node-positive patients in univariate analysis, also significantly added to the multivariate models for relapse-free and overall survival. There were no statistically significant interactions between the levels of cathepsin-D and any of the classical prognostic factors in analysis for relapse-free survival, suggesting that the prognostic value of cathepsin-D is not different in the various subgroups of patients. Indeed, multivariate analyses in subgroups of node-negative and -positive patients, pre- and post-menopausal patients, and their combinations, showed that tumours with high cathepsin-D values had a significantly poor relapse-free survival, with relative hazard rates ranging from 1.3 to 1.5, compared with tumours with low cathepsin-D levels. The results presented here on 2810 patients confirm that high cytosolic cathepsin-D values are associated with poor prognosis in human primary breast cancer.     

Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: electrophysiological evidence

Behavioral nociceptive responses evoked by relatively high rates of noxious radiant skin heating appear to be mediated by A delta nociceptor activation, whereas responses evoked by low rates of skin heating appear to be mediated by the activation of C-fiber nociceptors. This hypothesis was confirmed by the results of single unit recordings of A delta and C nociceptive afferent fibers isolated from the saphenous nerves of pentobarbital anesthetized rats. Heating the hind paw skin of the rat at a relatively high rate of 6.5 degrees C/sec activated A delta units within 2 sec after the onset of the stimulus. This response latency is similar to the 2.5 sec latency of the foot withdrawal response to a similar stimulus. In contrast, C-fibers were only slightly activated at a longer latency of 5-6 sec. Conversely, heating the hind paw skin at a relatively low rate of 0.9 degrees C/sec activated C-fibers, but evoked only a few action potentials in A delta nociceptors. C-fibers began firing at a rate less than 1 Hz between 8 and 10 sec after the onset of heating and fired at a mean rate of 1.5 Hz between 10 and 12 sec, which corresponds to the latency of the foot withdrawal response. Topical application of capsaicin to the hind paw skin decreased the latency of C-fiber responses from control values of 8-12 sec to approximately 4 sec after topical capsaicin treatment. The mean latency of the foot withdrawal response to skin heating at the low rate is also reduced from control values of 12-14 sec to 4-5 sec after capsaicin treatment. In contrast, capsaicin treatment did not significantly affect the responses of A delta nociceptors. These results support the conclusion that nociceptive foot withdrawal responses to a low rate of skin heating are mediated predominantly by the activation of C-fiber nociceptors. These results provide direct evidence that, under the conditions of these experiments, nociceptive foot withdrawal responses evoked by high rates of skin heating are primarily mediated by A delta nociceptors, and foot withdrawal responses evoked by low rates of skin heating are primarily mediated by C-fiber nociceptors.