Synergistic interactions between nicotine and cocaine or methylphenidate depend on the dose of dopamine transporter inhibitor

There is a greater prevalence of cigarette smoking among cocaine-dependent individuals and hyperactive children treated with stimulants (e.g., methylphenidate, MP). However, little is known about the neurochemical basis of the interaction between nicotine and cocaine or MP. It is thought that the reinforcing effects of cocaine and MP are due partly to increases in synaptic DA in the nucleus accumbens (NAc). These measurable increases are secondary to the blockade of the DA transporter. In contrast, nicotine stimulates acetylcholine receptors located presynaptically on dopaminergic projections from the ventral tegmental area (VTA) to the NAc and increases DA transmission. Here we investigate the effects of nicotine on NAc DA in animals simultaneously injected with cocaine or MP. Coadministration of nicotine (0.4 mg/kg s.c.) and cocaine (10 mg/kg i.p.) or MP (5 mg/kg i.p.) increased the extracellular NAc DA levels in an additive manner, while coadministration of nicotine (0. 4 mg/kg s.c.) and a higher dose of cocaine (20 mg/kg) or MP (10 mg/kg) clearly produced a synergistic elevation in NAc DA. These findings suggest that the degree of DA transporter (DAT) occupancy contributes to the synergistic interaction between nicotine and cocaine or MP.     

Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B.

PURPOSE: Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza C) was active in patients with high-risk MDS. PATIENTS AND METHODS: A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m(2)/d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C. RESULTS: Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P <.001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P =.007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P =.001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P =.03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C. CONCLUSION: Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study.     

A rare case of ceruminous tumor of the cerebellopontine angle

In this case report we describe the development in the cerebellopontine angle of a very rare tumor, ceruminous adenoma. In the few cases described in the literature this tumor occurred in the external acoustic meatus. In four cases it developed in the cerebellopontine angle by infiltration of the petrous bone or by subcutaneous spread. In the present case no connection was found between the cerebellopontine angle and the external acoustic meatus. The most likely pathogenetic hypothesis in this case is that of a tumor of dysembryogenetic origin.     

Ubiquitin and neurofilament expression in anterior horn cells in amyotrophic lateral sclerosis: possible clues to the pathogenesis

Cytoskeletal abnormalities are a prominent pathological feature of anterior horn cells in amyotrophic lateral sclerosis (ALS), and are thought to be involved in the process of motor neuron death. Skein–like filamentous inclusions have been detected by immunocytochemical staining for ubiquitin, a stress protein involved in targeting abnormal proteins for proteolysis. So far, identification of the target protein has been elusive. We have studied the ultrastructural localization of ubiquitin and neurofilaments by post–embedding immunogold staining. In skein–like arrays, strong ubiquitin labelling was concentrated on abnormally formed 15–20 nm filaments; neurofilament labelling was localized on 10 nm filaments adjacent or in continuity with the abnormal filaments. In addition, Bunina bodies were a major site of ubiquitin accumulation. Our results suggest that ubiquitinated filaments in skein–like inclusions might originate from abnormally aggregated neurofilament proteins, which are no longer recognized by antibodies to neurofilament epitopes. Furthermore, the presence of ubiquitin in Bunina bodies suggests that, in addition to its protective role, ubiquitin might be directly implicated in the mechanism of programmed neuronal death in ALS.     

Promyelocytic blast crisis in chronic granulocytic leukemia with 15;17 translocation

A patient with Philadelphia chromosome Ph¹-positive chronic granulocytic leukemia (CGL) developed an acute transformation associated with a hemorrhagic diathesis and bone marrow infiltration by hypergranular promyelocytes and blasts. Cytogenetic analysis of bone marrow metaphase cells at transformation showed a t(15;17) superimposed upon the Ph¹-positive cell line. These findings suggest a critical relationship between the t(15;17) and arrest of myeloid leukemic cell differentiation at the promyelocyte stage.     

Exogenes halluzinatorisches Syndrom mit Wahnbildung als Psychose-Modell

Zusammenfassung Eine Halluzinose bei ausgedehntem suprasellären (Hypophysen-?) Tumor einer 54 Jahre alten Frau, wird als Psychose-Modell vorgestellt, dessen komplexe Struktur einer mehrdimensionalen Analyse unterzogen wird.Die verschiedenen Stadien des halluzinatorisch-paranoiden Krankheitsbildes, in dem die charakteristischen Zeichen einer sogenannten exogenen Psychose fehlten und auch ein sogenanntes organisches Psychosyndrom sich nicht herausschälen ließ, waren im wesentlichen von der Veränderung der Ich-Umweltbeziehung, d. h. vom Grad des Verstricktseins in das psychotische Erleben, abhängig. Wir gebrauchen hierfür den Terminus Involvierung und unterstellen, daß eine zunehmende Involvierung die Bewußtseinseinengung (die Faszination) herbeiführt und daß die zunehmende Einengung kein primäres Phänomen ist, wie dies im Schrifttum mitunter vertreten wird. Es kommt im Zuge der Auseinandersetzung mit den psychotischen Erlebnissen stufenweise zu einer immer stärkeren Verstrickung und schließlich zu einem Aufgehen in einer anderen Wirklichkeit. Das Emotionale ist dabei sicherlich eine wesentliche Komponente. Die paranoide Wahnstimmung (Das Trema usw.) stellt ein umschriebenes, aber emotional wenig strukturiertes Radikal im menschlichen Verhalten dar. Bei unserem Falle ist noch der Erlebniswandel des hochgradig Schwachsichtigen mit seinen vegetativen Umstimmungen von großer Bedeutung. In diesem Zusammenhange wird auf die physiologischen Gesichtspunkte, insbesondere auf die Rolle des vegetativen Systems im weiteren Sinne bei der Entstehung halluzinatorischer Syndrome hingewiesen, aber auch auf die Bedeutsamkeit der Daseinsordnungen, insbesondere der Wohnordnung.Das Thema des Wahns erfährt seine Ausgestaltung durch die Konstitution und in bezug. auf die individuelle Biographie, die somit in unserem Falle eher als pathoplastische Faktoren und nicht als wesentliche pathogenetische Momente imponieren.Soweit eine Lokalisationsbeziehung bei exogenen psychotischen Syndromen diskutiert werden kann, erscheint die Beteiligung des Hirnstammes und speziell des retikulären Systems am ehesten wahrscheinlich. Ausdrücklich wäre darauf hinzuweisen, daß sich die Art der seelischen Erkrankung auch bei diesen Fällen nicht schablonenhaft aus Art und Sitz des Hirnprozesses ergibt.Herrn Prof. Dr. H. Kranz zum 60. Geburtstag gewidmet.     

Analysis of some factors effecting survival in malignant gliomas.

Many factors, including the histological aspect, are known to effect the survival of patients with malignant gliomas. The relation between survival and diagnoses such as primary and secondary glioblastoma, anaplastic astrocytoma, etc., is not definitely clear. In 324 malignant gliomas the relationship between survival and age, sex, tumor pathology, occurrence of lymphoplasmacytic infiltrations, and size of the examined specimen was studied. Preoperative intervals of primary and secondary glioblastomas do not differ; anaplastic astrocytomas show definitely longer preoperative intervals and slightly but not significantly longer postoperative patient survival. The correlations are discussed, focusing on importance of knowing the survival times of untreated cases in order to evaluate the efficacy of chemotherapeutic drugs in malignant gliomas.