Differential elimination of circadian and ultradian rhythmicity by hypothalamic lesions in the common vole, Microtus arvalis.

Effects of hypothalamic lesions on the ultradian and circadian organization of wheel running and feeding were studied in the common vole, Microtus arvalis. Circadian organization broke down within 30 days in continuous darkness in 24% of intact voles (n = 135). Ultradian rhythmicity of feeding (period 2-3 hr) persisted in constant conditions in all intact voles. Following lesions of the suprachiasmatic nuclei (SCN), circadian rhythmicity disappeared when lesions were complete (n = 8) or more extensive than 25% of the total SCN volume (n = 5). Absence of circadian rhythmicity was also found in animals with substantial lesions in the diencephalic paraventricular area (PVA) and in the retrochiasmatic area (RCA) and/or adjacent arcuate nucleus (Arc). Complete loss of ultradian and circadian organization occurred in eight voles with damage to the RCA and/or Arc. In three of these, the SCN was intact. The SCN is a likely candidate for a circadian pacemaker in voles (as in other rodents), while the loss of circadian rhythmicity following PVA and RCA/Arc lesions may be due to destruction of efferent pathways from the SCN. The RCA/Arc area is apparently necessary for the expression of ultradian rhythms. The intact SCN is neither necessary nor sufficient for the generation of ultradian rhythmicity.

Responsiveness of suprachiasmatic and ventral lateral geniculate neurons to serotonin and imipramine: a microiontophoretic study in normal and imipramine-treated rats.

The suprachiasmatic nuclei (SCN) are a major pacemaker of circadian rhythms in mammals. The SCN receive a direct retinal projection and a second optic input via the ventral lateral geniculate nucleus (vLGN). Both visual pathways mediate the entrainment of circadian rhythms, whereas both the SCN and the vLGN receive serotonergic afferents from the raphe nuclei. We investigated the effects of microiontophoretically applied serotonin (5HT) on SCN and vLGN cells in normal rats and rats chronically treated with the 5HT reuptake blocker imipramine (IMI). In the SCN of both groups over 40% of all recorded cells (N = 80) responded to 5HT with a dose-dependent suppression of their spontaneous or glutamate-evoked discharge, while twenty percent were tonically light-responsive. Except for one cell with an inconsistent 5HT response, none of the visual SCN neurons were 5HT-sensitive. In the vLGN of normal and IMI-treated rats about 60% of the cells recorded (N = 42) were inhibited by 5HT. In IMI-treated rats a few cases of excitation by 5HT were encountered in the vLGN. Visual as well as non-visual vLGN cells were responsive to 5HT. Microiontophoretic application of IMI resulted in suppression of electrical activity in both brain regions and enhanced the response induced by 5HT. Chronic IMI-treatment produced a significant increase in the sensitivity of cells in the SCN and vLGN to iontophoresed 5HT, without affecting the relative magnitude of the inhibition. The recovery from 5HT-induced inhibition was slow in these animals. Interestingly, the spontaneous discharge rate of both 5HT-sensitive and 5HT-insensitive SCN and vLGN cells was significantly lower in the imipramine-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Luminance coding in a circadian pacemaker: the suprachiasmatic nucleus of the rat and the hamster.

The hypothalamic suprachiasmatic nuclei (SCN) of mammals function as a pacemaker driving circadian rhythms. This pacemaker is entrained to the daily light-dark cycle in the environment via the retina and central retinal projections to the anterior hypothalamus. We carried out a comparative study of the visual properties of rat and hamster SCN neurons. Extracellular single cell activity was recorded in the SCN of urethane-anaesthetized animals. In both species, visual SCN neurons responded to retinal illumination with a sustained increase or a sustained decrease in electrical discharge. The majority (75%) of these cells were activated by light. In both the rat and the hamster SCN, visually responsive cells altered their discharge rate as a monotonic function of luminance. The intensity-response curve could be described by a Michaelis function with a small working range between threshold and saturation (2-3 log units) and a relatively high threshold. Intensity-response curves in both species were occasionally different for increasing as opposed to decreasing luminance. Thus, hysteresis effects of illumination may occur in the SCN. The spontaneous firing rates as well as the responsiveness of visual SCN cells were subject to marked variations between and within cells. The overall photic responsiveness of SCN neurons, however, indicated that they are specialized for luminance coding in the range of light intensities naturally occurring at dawn and dusk. This property makes these cells suitable to mediate photic entrainment of circadian rhythms as well as the measurement of photoperiod.

Phase-I study of mafosfamide-cyclohexylamine (ASTA-Z-7557, NSC 345 842) and limited phase-I data on mafosfamide-lysine.

Mafosfamide-cyclohexylamine is a new oxazaphosphorine derivative. It was chosen for phase-I clinical testing because of an expected higher therapeutic index and lack of complete cross resistance in animal tumors compared to cyclophosphamide. The schedule consisted of a single iv dose repeated every three weeks. The compound was found to cause as it's dose limiting toxicity severe pain along the injected vein and acute irritation of mucous membranes. The maximal tolerated dose was around 1000 mg/m2 given as a slow infusion over 2-3 hours. Hematological toxicity was mild. A limited phase-I study with the lysine salt of mafosfamide showed an identical type of toxicity. Mafosfamide given iv in a high-dose intermittent schedule is of little interest for further clinical trials. It is probable, that the severe venous pain and the mucosal irritation are caused by the high local concentration of 4-hydroxy-cyclophosphamide or by a metabolite. An oxazaphosphorine derivative undergoing slower hydrolysis therefore leading to lower active drug concentrations within the injected vein may be more promising.

Microangiopathic hemolytic anemia, a frequent complication of mitomycin therapy in cancer patients.

Microangiopathic hemolytic anemia (MAHA) has long been recognized as a rare complication in far-advanced malignant tumors. Recently several patients have been described in whom MAHA and renal insufficiency developed as a result of mitomycin therapy. We here describe another five such cases among 50 patients treated with mitomycin. All five cases were observed among the 14 patients who had received four or more doses of the drug. We conclude that MAHA is a frequent and potentially fatal complication of long-term mitomycin treatment. Careful monitoring for the early appearance of schistocytes is mandatory as the syndrome tends to be self-limited if this therapy is discontinued early.

Lack of response in nine patients with breast cancer treated with fibroblast interferon.

Nine patients with metastatic breast cancer were treated with a minimum of 6 X 10(6) U/day of beta-interferon (IFN-beta) for at least 6 weeks. In patients whose disease did not progress during this period treatment was continued to a maximum of 13 weeks, while in other patients doses were escalated. With daily treatments over 3 weeks the maximum tolerated dose was found to be around 60 X 10(6) U/day. Fever occurred regularly. The dose-limiting toxicities were granulocytopenia and increasing liver enzymes. No objective remissions were observed. One patient showed stable disease after her cancer en cuirasse had rapidly progressed under chemotherapy. One patient each with nasopharyngeal carcinoma and fibrous sarcoma were also treated without success. IFN-beta at this moderately toxic dose given over a period of 6-13 weeks is of no clinical value in the treatment of metastatic breast cancer in women.

The effect of sleep deprivation on sleep in rats with suprachiasmatic lesions.

The effect of 24-h sleep deprivation on sleep was investigated in rats whose circadian rest-activity rhythms were extensively disrupted by bilateral lesions of the suprachiasmatic nuclei (SCN). Sleep deprivation caused an increase in total sleep, REM sleep and the slow wave sleep fraction of non-REM sleep. It is concluded that the homeostatic component of sleep regulation is morphologically and functionally distinct from the circadian component.

Electrical and pharmacological properties of the suprachiasmatic nuclei.

The suprachiasmatic nuclei (SCN) of the mammalian hypothalamus are in important circadian pacemaker. The electrical activity of these nuclei exhibits an intrinsic circadian rhythm. The rhythmicity of the SCN is also reflected in cyclic glucose consumption and serotonin metabolism. These rhythms are entrained to the light-dark cycle via the retinohypothalamic projection. This pathway, possibly together with a visual projection via the ventral lateral geniculate nuclei, innervates light-responsive SCN cells, which exhibit the functional properties of luminance detectors. The SCN contain various peptides, acetylcholine, and serotonin either intrinsically or in terminals of afferent projections. For acetylcholine it has been demonstrated that the SCN mediate the process of photic entrainment and light suppression of pineal synthetic activity. In the case of serotonin and vasopressin it seems certain that the SCN do not depend on their presence for generating circadian rhythms or for entrainment. Both substances may modulate the intrinsic pacemaker frequency through mechanisms that remain to be established.

Circadian rhythms in electrical discharge of rat suprachiasmatic neurones recorded in vitro.

The discharge of suprachiasmatic (SCN), retrochiasmatic (RCA) and arcuate (ARC) neurones was recorded in brain slices incubated for periods up to 30 h. The firing rate of cells in the SCN, but not in the RCA and ARC, exhibited a circadian rhythm similar to that reported for the SCN in freely moving animals. This rhythm cannot be ascribed to subtle exogenous diurnal variations in the incubation conditions. It is concluded that the SCN explant is capable of endogenous generation of at least one circadian cycle in vitro.

Suprachiasmatic stimulation phase shifts rodent circadian rhythms.

The integrity of the suprachiasmatic nuclei (SCN) of the hypothalamus is essential to the expression of normal circadian rhythms in rodents. Electrical stimulation of the SCN caused phase shifts and period changes in the freerunning feeding rhythms of rats and activity rhythms of hamsters. The phase response curve for SCN stimulation appears to parallel that for light pulses. These findings strengthen the hypothesis derived from lesion studies that the SCN are the dominant light-entrained oscillators in the rodent circadian system.

[Microangiopathic haemolytic anaemia as a complication of mitomycin C treatment (author's transl)]. / Mikroangiopathische hämolytische Anämie als Komplikation bei Mitomycin-C-Therapie.

Microangiopathic haemolytic anaemia developed in 5 (out of 14) patients treated with mitomycin C combinations, having received 4 or more treatment cycles. This finding necessitates restricted use of broad and longterm use of mitomycin C, particularly in view of the occasionally fatal outcome of this toxic complication. Adjuvant treatment with mitomycin C does not appear acceptable any longer. Patients treated with mitomycin C should be monitored carefully for occurrence of schistocytosis and platelet deficiency as very early signs of microangiopathic haemolytic anaemia.

Persistence of visual responsiveness in the lateral geniculate nucleus of rats treated with monosodium-L-glutamate.

Normal treatment of rats with monosodium-L-glutamate (MSG) resulted in extensive degeneration of the inner nuclear layer of the retina. The retino-hypothalamic projection was still functional as these rats entrained their circadian food intake rhythm to the light-dark cycle. A normal proportion of dorsal lateral geniculate nucleus (LGNd) cells in MSG rats responded to visual stimulation. The response pattern, latency and variability of LGNd cells at different times (3-18 months) after treatment were comparable to those of normal rats. These results demonstrate the MSG-induced retinal damage does not lead to blindness in the rat. The similarity in pathophysiology between MSG lesioned rats and animals exposed to constant illumination is discussed.

Cortico-recipient and tecto-recipient visual zones in the rat's lateral posterior (pulvinar) nucleus: an anatomical study.

Afferents to the lateral posterior (pulvinar) nucleus in the rat were studied anatomically using retrograde tracing with fluorescent and horseradish peroxidase techniques. Layer V pyramidal cells in cortical areas 17 and 18a were found to project to the rostral portion of the lateral posterior nucleus (LTP) (the cortico-recipient zone). Cells in the deep superficial grey of the superior colliculus projected to the caudal portion of the LTP (the tecto-recipient zone), the posterior pole of which also received input from cortical area 36. These findings agree with the notion that the rat's LTP is functionally equivalent to regions of the feline and primate pulvinar-complex.

[Complicated course of a percutaneous transluminal angioplasty (PTA) (author's transl)]. / Komplizierter Verlauf einer perkutanen Gefässrekanalisation.

In the course of a percutaneous transluminal angioplasty (PTA) of the superficial femoral artery three complications occurred: Perforation of the vessel at the occluded segment, embolisation of the truncus tibiofibularis and perforation of the truncus tibiofibularis during recanalization of the embolised segment. Despite these complications, it was possible to recanalize the original thrombotic occlusion of the superficial femoral artery and the embolic occlusion of the truncus tibiofibularis.

Functional absence of brain photoreceptors mediating entrainment of circadian rhythms in the adult rat.

The photic energy penetrating into the brain was increased in adult rats sustaining craniotomies sealed with transparent plastic. After blinding, these animals failed to entrain their circadian food intake rhythm to light-dark cycles. Short pulses of light did not phase-shift the freerunning rhythm. We conclude that adult rats lack brain photoreceptors mediating entrainment of circadian rhythms.