Human EGF receptor (HER) family and heregulin members are differentially expressed in epidermal keratinocytes and modulate differentiation.

Human EGF receptor (HER), also designated HER1, is an activatable tyrosine kinase receptor. HER1 activation regulates cell growth and differentiation in epidermal keratinocytes. Expression of other HER family members was investigated in human keratinocytes cultured under autocrine conditions. HER2 and HER3 are expressed and upregulated by confluence, concurrent with induction of epidermal differentiation. HER4 is not expressed by keratinocytes. Maximum expression of the cognate ligand, heregulin, is observed in subconfluent keratinocytes, and the expression of both heregulin alpha and beta isoforms is downregulated with confluence. Recombinant heregulin isoforms have no effect on colony formation and keratinocyte proliferation, but heregulin beta activates tyrosine phosphorylation of HER2 and HER3, with no effect on HER1, in confluent differentiating keratinocyte cultures. Also, heregulin beta increases HER2/HER3 heterodimerization under those conditions. Treatment of confluent cultures by heregulin beta correlates with cell signaling and inhibition of epidermal differentiation. Together, HER2, HER3, and heregulin constitute a potential autocrine-paracrine system involved in epidermal homeostasis and repair, as well as in hyperproliferative pathologies.

Regulation of a novel immediate early response gene, IEX-1, in keratinocytes by 1alpha,25-dihydroxyvitamin D3.

1alpha,25-Dihydroxyvitamin D3 [1alpha,25(OH)2D3] regulates cellular growth and differentiation. We show that in keratinocytes, 1alpha, 25(OH)2D3 reduces concentrations of the messenger RNA of IEX-1, the product of which blocks Fas- or tumor necrosis factor type alpha-induced apoptosis in various cells. In sub-confluent keratinocyte cultures, the addition of 1alpha,25(OH)2D3, in amounts that induce growth arrest, reduces IEX-1 mRNA concentrations. In confluent cells, 1alpha,25(OH)2D3 initially reduces and then increases IEX-1 mRNA concentrations. IEX-1 protein is localized in the nucleus and perinuclear region of keratinocytes. In sub-confluent cells, 1alpha,25(OH)2D3 translocates IEX-1 protein from the nucleus to the perinuclear region and cytoplasm. Since IEX-1 has recently been shown to regulate cell survival and number, we suggest that IEX-1 may play a role in keratinocyte growth and differentiation and that 1alpha,25(OH)2D3 may reduce keratinocyte growth via a reduction in IEX-1 mRNA and a change in the intracellular distribution of IEX-1 protein.

H2O2 is an important mediator of UVB-induced EGF-receptor phosphorylation in cultured keratinocytes.

Exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) radiation induces phosphorylation of the epidermal growth factor receptor (EGFR). We demonstrate that H2O2 generated by UVB mediates EGFR phosphorylation. Using dihydrorhodamine 123 as a specific fluorescent dye probe, we show that UVB irradiation (50-800 J per m2) of keratinocytes leads within minutes to concentration-dependent intracellular production of H2O2. A corresponding concentration-dependent increase in the release of extracellular H2O2 was measured by using Amplex, a derivative of dihydrophenoxazine. The levels of intracellular H2O2 that are induced by UVB irradiation and that stimulate EGFR phosphorylation correlate strongly with the response induced by exogenously added H2O2. UVB or H2O2 demonstrated concentration- and time-dependent stimulation of EGFR phosphorylation that was initially observed within 1-5 min and exhibited a proportionate delay for UVB-induced production of H2O2. EGFR phosphorylation induced by UVB or H2O2 declined significantly toward baseline levels by 4 h and could be restimulated after H2O2 but not after UVB exposure. Phosphorylation of EGFR was inhibited by the structurally unrelated antioxidants butylated hydroxyanisole, N-acetyl-L-cysteine, and pyrrolidine dithiocarbamate, or by the H2O2-degrading enzyme catalase. These data indicate that generation of H2O2 by UVB radiation of human keratinocytes participates in the rapid, ligand-independent phosphorylation of EGFR and implicate H2O2 as a biologic mediator in EGFR activation and regulation of the downstream signaling cascade. UVB-induced H2O2 has the potential to initiate or modulate early EGFR-mediated signaling events that could play an important role in the cellular response to oxidative stress.

Treatment of myelodysplastic syndromes with daily oral idarubicin. A phase I-II study.

BACKGROUND: Idarubicin, a new anthracycline analogue, is available in an oral preparation, and responses have been observed using relatively aggressive therapy in patients with myelodysplastic syndromes (MDS). The authors studied whether a chronic low-dose schedule would be effective but less myelotoxic. METHODS: Forty-two patients with MDS received daily low-dose oral idarubicin in 5-week courses that included 3 weeks of treatment, followed by a 2-week rest period. Doses were escalated when possible after the second course, and each patient was to receive six courses. RESULTS: Only one partial response was observed. Although no patient had fatal bone marrow toxicity, only eight patients received the full six courses, primarily because of myelosuppression. CONCLUSIONS: This schedule of oral idarubicin is relatively safe but produces fewer responses than are reported with the high-dose pulse regimens.

Buspirone and diazepam: comparison of subjective, psychomotor and biological effects.

The effects of oral buspirone (BUS, 10 mg) and diazepam (DZP, 10 mg) were studied in 12 healthy women volunteers using subjective ratings, objective tests of psychomotor and cognitive functions and urinary dosage of catecholamine output. Drugs were randomly administered to the same subjects, in a crossover, double-blind study, each drug administration being separated by at least 1 week. BUS subjective effects were less severe than those of DZP and not accompanied by feelings of sleepiness that characterized DZP sedative effects. Furthermore, BUS did not impair psychomotor functioning while DZP induced both an impairment of central sensory processing and, to a lesser extent, an impairment in delayed memory.

Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin.

We evaluated the psychiatric morbidity and mood characteristics of a group (n = 72) of patients with cystic acne before and after treatment with one of three dosage schedules of isotretinoin. Although no excess psychiatric morbidity was observed, substantial evidence of psychologic distress was noted before treatment. Significant reductions in anxiety were observed on several measures of anxiety after treatment, with mitigation of anxiety and depression most robust in those patients with the greatest dermatologic improvement with isotretinoin.

Metabolic and behavioral consequences of lidocaine-kindled seizures.

Daily administration of lidocaine results in progressive increases in frequency and duration of convulsions in response to a dose of drug which was previously subconvulsive--a pharmacological kindling phenomenon. The effects of such lidocaine-kindling on local cerebral glucose utilization were determined by the 2-[14C]deoxyglucose method. Lidocaine-treated animals, in the absence of convulsions, exhibited decreased glucose utilization in most brain structures compared to saline-treated animals and showed no increase in aggressive behavior. In animals displaying lidocaine-kindled convulsions there were marked increases in glucose utilization in either the hippocampus and amygdala or in perirhinal cortical areas during the seizure administration; these animals also displayed long-lasting increases in irritable behavior. Seizure duration was positively correlated with the rate of glucose utilization in the hippocampus, amygdala and septum, but inversely correlated in several non-limbic areas. These data suggest that lidocaine-kindled seizures are highly localized to limbic and perirhinal structures and are associated with important behavioral consequences.

Prophylactic efficacy of carbamazepine in manic-depressive illness.

Seven patients with rapidly cycling, lithium-resistant affective illness were followed for an average of 1.7 years during prophylactic treatment with carbamazepine administered on either a blind or an open basis. The number of manic and depressive episodes per year decreased significantly--from 16.4 before treatment to 5.6 during carbamazepine treatment; severity and duration of episodes were also reduced. Six of seven patients relapsed after carbamazepine dose reduction or discontinuation. These preliminary data add further support to the growing evidence that carbamazepine may be useful in the acute and prophylactic treatment of some lithium-resistant patients.

Effect of lidocaine pretreatment on cocaine-induced behavior in normal and amygdala-lesioned rats.

Animals treated with daily lidocaine (60 mg/kg, i.p.) develop progressive increases in pathological eating of nonnutritive substances, i.e. omniphagia. Bilateral amygdala lesions blocked the development of lidocaine-induced omniphagia. Following 32 daily injections of lidocaine, both lesioned and nonlesioned animals showed greater cocaine-induced hyperactivity than saline-pretreated controls. These data suggest cross-sensitization between the two local anesthetics lidocaine and cocaine, even though lidocaine does not possess the psychomotor stimulant effects of cocaine. Amygdala-lesioned animals showed greater cocaine-induced vertical rearing activity compared to controls. The lesion data suggest that the amygdala is differentially involved in the progressive behavioral sensitization to both chronic lidocaine and cocaine.

The effect of amygdala kindling on spontaneous and cocaine-induced motor activity and lidocaine seizures.

Interactions of amygdala kindling and drug effects were explored in two experiments. Pretreatment with cocaine (40 mg/kg, IP) for 10 days did not significantly affect the rate of amygdala kindling compared to saline or non-kindled controls. In contrast, daily amygdala kindling with 200 microA for 0.5 s for 20 days substantially altered subsequent behavioral responses in a long-lasting fashion. Animals showed decreased spontaneous vertical rearing activity, as well as decreased cocaine-induced vertical activity. In contrast, they were more reactive to the direct dopamine receptor agonist apomorphine. Eighteen days following completion of amygdala kindling, kindled animals were more sensitive to lidocaine-induced convulsions; 88% of kindled animals, but only 24% of the implanted sham-stimulated controls, had seizures. These data suggest that amygdala kindling may produce long-lasting changes in selected spontaneous and drug-induced behaviors, as well as convulsive thresholds. Possible physiological and neurological changes underlying this altered responsivity are discussed.