Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes.

We investigated the effect of all-trans-retinoic acid (atRA) on proliferation in several human skin cell lines and found that antiproliferative potency of atRA correlated with the endogenous activity of canonical Wnt signaling. In HaCaT keratinocytes, we found that atRA significantly suppressed the expression of Id2, a member of the inhibitor of differentiation family of transcription factors that regulate cell growth and differentiation. However, no apparent change in the expression of other Wnt targets, like c-Myc or cyclin D1, was observed. Retinoid-induced Id2 gene suppression was associated with decreased levels of histone H3 and H4 acetylation and histone H3 Lys-4 methylation, and with recruitment of the LSD1 demethylase at the Wnt-response element (WRE) (TCF/LEF-binding site), in the Id2 gene promoter. None of such changes was detected at the WRE of c-Myc and cyclin D1 gene promoters. Inhibition of Id2 by short interfering RNA (siRNA) had a similar effect on the proliferation of HaCaT cells as exposure to atRA, whereas anti-beta-catenin siRNA significantly inhibited its antiproliferative effect. These data suggest that downregulation of Id2 gene expression through transcriptional convergence between Wnt and retinoid signaling pathways underlies the antiproliferative effect of retinoids in keratinocytes, and provide evidence of gene-targeted crosstalk between signaling pathways.

Alteration of a single amino acid in peroxisome proliferator-activated receptor-alpha (PPAR alpha) generates a PPAR delta phenotype.

Three pharmacologically important nuclear receptors, the peroxisome proliferator-activated receptors (PPARs alpha, gamma, and delta), mediate key transcriptional responses involved in lipid homeostasis. The PPAR alpha and gamma subtypes are well conserved from Xenopus to man, but the beta/delta subtypes display substantial species variations in both structure and ligand activation profiles. Characterization of the avian cognates revealed a close relationship between chick (c) alpha and gamma subtypes to their mammalian counterparts, whereas the third chicken subtype was intermediate to Xenopus (x) beta and mammalian delta, establishing that beta and delta are orthologs. Like xPPAR beta, cPPAR beta responded efficiently to hypolipidemic compounds that fail to activate the human counterpart. This provided the opportunity to address the pharmacological problem as to how drug selectivity is achieved and the more global evolutionary question as to the minimal changes needed to generate a new class of receptor. X-ray crystallography and chimeric analyses combined with site-directed mutagenesis of avian and mammalian cognates revealed that a Met to Val change at residue 417 was sufficient to switch the human and chick phenotype. These results establish that the genetic drive to evolve a novel and functionally selectable receptor can be modulated by a single amino acid change and suggest how nuclear receptors can accommodate natural variation in species physiology.

Autoimmune hemolytic anemia in allergic granulomatous angitis (Churg-Strauss syndrome).

We describe a patient with allergic granulomatous angitis who developed autoimmune hemolytic anemia (AIHA). A 44-year-old male had been suffering from bronchial asthma. On admission, laboratory tests revealed the presence of severe eosinophilia (21,500/microliters), elevation of total immunoglobulin E (IgE), high lactic dehydrogenase (LDH) and low haptoglobin levels, in addition to moderate reticulocytosis. During admission, the patient showed almost simultaneous occurrence of vasculitis in the extremities, severe hemolysis and exacerbation of asthma in relation to the progression of eosinophilia. Both IgM and IgG autoantibodies were considered to be responsible for hemolysis. Interestingly, serum levels of interleukin-4 (IL-4) and IL-5 were increased in association with eosinophilia and increased IgE production. These findings suggest that the AIHA in this patient is mediated or enhanced at least partly by high IL-4 and IL-5 production. Although AIHA in this syndrome is very rare, it should be considered as a clinical manifestation.

Effects of somatostatin deficiency on cell distribution within the Langerhans islets.

Insulin, glucagon and somatostatin (SLI) in the pancreas and the gastrointestinal tissue of rats were measured following a high (300 mg/kg) or low (150 mg/kg) dose of cysteamine, given intermittently for 14 days. In addition, the effect of prolonged cysteamine-induced depletion of pancreatic SLI upon the cell distribution within the Langerhans islets was compared with that of chronic insulin-deficient rats produced by streptozotocin. The high or low dose of cysteamine reduced pancreatic SLI to 8.3% and gastrointestinal SLI to 5.6% of control levels without duodenal ulcer. The high dose of cysteamine also reduced pancreatic insulin to 37% of controls without hyperglycemia. No change in the glucagon concentration was observed. In SLI-deficient rats, distribution of A and B cells was similar to that of controls, even though D cells were rarely seen. In insulin-deficient rats, however, the number of A and D cells per islet area increased with a concomitant decrease in B cells. Intermittent administration of a low dose of cysteamine, thus, appears to be useful to produce a chronic SLI-deficient rat. However, a high dose of cysteamine is not a specific depletor of pancreatic SLI. Although insulin may be important to maintain normal cell distribution within the islets, pancreatic SLI may not have such a role.

[On the phenomena of extravasation of contrast media in cerebral angiogram of the case of hypertensive intracerebral hematoma and their clinical significance-analysis of 14 cases (author's transl)]?

Since Westerburg (1966) reported a case of hypertensive intracerebral hemorrhage who showed extravasation of contrast media on the cerebral angiogram, only 21 cases demonstrated extravasation of contrast media were reported by several authors. The author experienced 14 cases of hypertensive intracerebral hemorrhage whose cerebral angiogram showed extravasation of contrast media. These 14 cases occupied 21.1% of 58 cases whom cerebral angiographies were performed within 24 hours after the stroke. 6 out of 14 cases were cured by evacuation of the hematoma surgically. These 14 cases were dividied into three types by the shape of extravasation of contrast media as followed: Type I showed widespread leakage of contrast media. Type II showed sash-like leakage of contrast media surrounded by diffuse thin shadow and Type III showed small spotlike leakage of contrast media. These three types indicated the arterial bleeding stage, the stage of accerelated arterial wall permeability and the subsquent venous bleeding respectively. The author concluded that these extravasation of contrast media not only demonstrated the bleeding artery but also indicated the process of the hematoma formation in each case.

[A cured case of hypertensive intracerebellar hematoma (author's transl)].

A case of hypertensive intracerebellar hematoma surgically treated and cured was reported. The 41-year-old male had two cerebrovascular attacks with headache and vomiting followed by left hemiparesis. Drowsiness and dysarthria appeared the next day. The patient was admitted to a hospital, where right facial palsy, loss of right gag reflex and paralytic hemiplegia on the left side were noted. On the 7th day, the patient's consciousness became clear byt the other neurological evidences did not change. On the 14th day, bradycardia and central hyperventilation appeared and he became drowsy again. The patient was transferred to the authors' clinic. When the patient was admitted, he showed typical cerebellar signs such as nystagmus, ataxia, and slurring speech with pyramidal sign on left side and cranial nerves paralysis on right side, and also showed the changes of vital signs as a medullary syndrome in the late stage of the course. The vertebral angiogram revealed a space taking process in the right cerebellar hemisphere. The old blood (30g) was removed by suboccipital craniectomy. The hematoma cavity had a communication with the IVth ventricle through a small perforation in the medial wall of the hematoma. Spontaneour intracerebellar hematoma including of hypertensive origin is not rare in the reports of autopsy but surgically treated case has only rarely been reported. The main reason of few survivals should be in its fulminate course.

[DS-bronchial arteriography; demonstration of metastasized lymphnodes of lung cancer--with special reference to the primary effect in BAI].

We analysed the 44 DS-Bronchial arteriograms (DSBAG) of lung cancer with an attention to the demonstration of metastasized mediastinal lymphnodes. The stain of lymphnode is well demonstrated in the pericarinal region, such as station #7, #R4 along the course of bronchial arteries. The swollen nodes with stains on DSBAG show the good reduction rates (37.5%) after BAI that is analogous to the primary lesion (38.9%), in contrast to the nodes without stains (24.5%). DSBAG with excellent contrast resolution contributes to the BAI as verifying the infused area.

[MR imaging for lung cancer in evaluating local invasion; referring to CT and surgical-histological basis].

The diagnostic potentiality of MR imaging for lung cancer was researched in 17 patients in evaluating local invasions based on surgical-histological evidence. Comparative reviewing with CT was also performed. MR imaging appeared to have an ability unique to portray malignant invasions somewhere such as in the hili or apices. On the other hand, there were also some diagnostic limitations of MR imaging in delineating the localized invasive changes. On the way of working up lung cancer, CT still may stand at the first choice as a radiographic staging procedure which provides the more detailed anatomic-pathologic informations. We consider that MR imaging is mandatory when CT and/or other modalities could'not obtain efficient results.

[CT of hypersensitivity pneumonitis].

High resolution computed tomography (CT) was applied to seven patients with hypersensitivity pneumonitis clinically confirmed. The CT findings include; (1) granular pattern with acino-centric distribution, (2) increase in density of haziness in the lung fields, (3) multiform high density areas, and (4) "subpleural curvilinear shadow" localized posteriorly. Of these findings, which severally varied degree during clinical course, the haziness showed the most remarkable fluctuation. It was especially of interest that the relapsed haziness distributed quite in the same regions. High resolution CT may be an effective adjuvant tool for hypersensitivity pneumonitis when applied to the opportune evaluation through the clinical course.

[High resolution computed tomography of diffuse interstitial pneumonia during treatment].

HRCT was carried out in twenty patients with diffuse interstitial pneumonia: 13 cases of IIP, 3 of BOOP, 2 of drug-induced pneumonia, 1 of rheumatoid lung and acute interstitial pneumonia of unknown origin. With special attention to inflammatory activity, the patients underwent HRCT periodically during the treatment. Correlative investigation between HRCT image and grade of accumulation in 67Ga scintigraphy was also performed. Response to steroid therapy was clearly reflected on HRCT image, that was shown as decreasing pulmonary density or thinning of honeycomb wall. HRCT is considered to be useful in assessing the activity of diffuse interstitial pneumonia.