Hepatocyte nuclear factor (HNF)-4alpha induces expression of endothelial Fas ligand (FasL) to prevent cancer cell transmigration: a novel defense mechanism of endothelium against cancer metastasis.

Endothelial Fas ligand (FasL) contributes to the "immune privilege" of tissues such as testis and eye, in which apoptosis is induced in infiltrating Fas-positive activated T cells and results in the inhibition of leukocyte extravasation. In this study, we examined the role of endothelial FasL in controlling cancer cell transmigration using rat lung endothelial (RLE) cell line bearing a doxycycline-inducible hepatocyte nuclear factor (HNF)-4alpha expression system. We showed that a detectable level of FasL was expressed in RLE cells and that this expression was markedly up-regulated and well correlated to the degree of HNF-4alpha expression in a time-dependent manner. When various cancer cells were overlaid on an RLE monolayer sheet, we examined the ability of endothelial FasL to induce massive apoptosis in Fas-expressing cancer cells and found a causal link to inhibition of the transmigration. Finally, we showed that FasL was expressed in capillaries of the rat brain by immunohistochemical staining, suggesting that FasL serves its functions not only in vitro, but also in vivo. These results raise the possibility that HNF-4alpha is involved in regulating cancer cell transmigration by modulating the Fas-FasL system.     

Improvement of both psychotic symptoms and Parkinsonism in a case of dementia with Lewy bodies by the combination therapy of risperidone and L-DOPA

A 69-year-old female of dementia with Lewy bodies (DLB) with fluctuating cognitive impairment, visual and auditory hallucinations, persecutory delusions and Parkinsonism was treated by the combination of 1 mg/day risperidone and 300-750 mg/day L-DOPA. By this combination therapy, both the psychotic symptoms and Parkinsonism improved, while cognitive function did not deteriorate. This report suggests that the combination therapy of risperidone and L-DOPA may be worth considering in the special cases of DLB.     

CTG triplet repeat expansion in a laryngeal carcinoma from a patient with myotonic dystrophy

A 66-year-old Japanese man with myotonic dystrophy (DM) underwent total laryngectomy for laryngeal carcinoma. The size of the expanded DNA fragment (EF) from the leukocytes and normal laryngeal tissues of this patient was only slightly longer than that in normal subjects. EF, however, was markedly longer in the laryngeal carcinoma. These findings support the hypothesis that elongation of the CTG repeat in the DM kinase gene occurs during acquired cell proliferation.     

Effect of potassium channel openers on hypoxic pulmonary vasoconstriction]

The ATP-sensitive potassium channel (K+ATP) has been suggested as an important mechanism for the reactivity of vascular smooth muscle. We investigated the effects of K+ channel openers (lemakalim, pinacidil) on hypoxic pulmonary vasoconstriction (HPV) and angiotensin II (Ag II) induced vasoconstriction in isolated rat lungs (Sprague-Dawley rats: 300-450 g). Ventilation with hypoxic gas (2% O2, 5% CO2) was performed for 6 min after the injection of Ag II (0.1 microgram). Isolated lungs were perfused under constant flow (0.04 ml/g/min) using 20 ml of blood from donor rat. The perfusion pressure was used as the pulmonary artery pressure. Lemakalim or pinacidil was pre-administered through the reservoir. Pretreatment with pinacidil (10(-4) M) or lemakalim (10(-5) M) inhibited the pressor response to hypoxia, but did not inhibit the response to angiotensin II. Although the effect of lemakalim on HPV was reversed by administration of glibenclamide (10(-5) M) or tolbutamide (10(-3) M), the effect of pinacidil on HPV was not influenced by either drug. These results suggest that 1) K+ channel openers (lemakalim and pinacidil) inhibit the pressor response to hypoxia, and 2) lemakalim seems to act through K+ATP, whereas pinacidil may have other mechanisms of inhibition of vascular smooth muscle contraction. K+ATP may play an important role in the regulation of pulmonary vascular reactivity to hypoxia.     

Subclasses of olfactory receptor cells and their segregated central projections demonstrated by a monoclonal antibody

A library of monoclonal antibodies (MAbs) was generated against a homogenate of the rabbit olfactory bulb. One of them immunohistochemically distinguished a subgroup of olfactory nerves. Both in the olfactory bulb and the epithelium, this MAb labeled most olfactory receptor axons in the lateral but only a small fraction in the medial portion. These findings demonstrate a molecular heterogeneity among olfactory receptor cells and suggest a functional division between the lateral and the medial portions of the epithelium and the bulb.     

Vesicourethral Dysfunction Following Radical Surgery for Rectal Carcinoma: Change in Voiding Pattern on Sequential Urodynamic Studies and Impact of Nerve-Sparing Surgery

Objectives Urodynamic studies were performed to clarify vesicourethral dysfunction and recovery after rectal surgery for cancer.
Materials and Methods At 1, and 6 to 12 months after rectal surgery interviews and urodynamic studies (UDS) were performed on 51 consecutive patients, all without a prior history of voiding disorder (40 males and 11 females; median age, 60 years). Patients were divided into 2 groups, either with (preserved group, n = 17) or without (nonpreserved group, n = 34) preservation of the bilateral pelvic plexus during surgery. Comparisons of voiding status and urodynamic parameters were made between the 2 groups.
Results By 1 and 6 months after the operation normal voiding was achieved in 71 % (12/17) and 100% (13/13) of patients in the preserved group, and 6% (2/34) and 30% of patients (9/30) in the nonpreserved group, respectively (P< 0.001). Attainment of normal voiding in the nonpreserved group was preceded by the recovery of bladder sensation, while UDS demonstrated increases in vesical compliance and the disappearance of vesical denervation supersensitivity.
Conclusion A nerve-sparing procedure during radical surgery for rectal carcinoma preserved vesicourethral function. The urodynamic parameters relevant to postoperative recovery of voiding function were improved vesical compliance, disappearance of vesical denervation supersensitivity, and recovery of a bladder filling sensation.     

Blockade of dopamine D1 receptors by SCH 23390 antagonizes discriminative stimulus effects of pentazocine

The purpose of this investigation was to test the hypothesis that the discriminative stimulus properties of pentazocine are mediated through an interaction with dopamine receptors. Rats were trained to discriminate s.c. injections of pentazocine (3.0 mg/kg) from vehicle in a two-choice discrete trial avoidance paradigm. SCH 23390 (0.003–0.056 mg/kg), a selective antagonist of dopamine D₁ receptors, inhibited the discriminative stimulus effects of pentazocine in a dose-dependent fashion, whilst the selective D₂ receptor antagonist sulpiride (20.0–80.0 mg/kg) did not antagonize them. It appears that the dopamine D₁ receptors play an important role in the discriminative stimulus effects of pentazocine.     

The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death

Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine / threonine kinase and participates in a signaling complex that regulates both proliferation and apoptosis to ensure the proper size and shape of the fly. Human counterparts of this complex have been found to be frequently downregulated or mutated in cancers. WARTS, a human homolog of Wts, is also known as tumor suppressor and mitotic regulator, but its molecular implications in tumorigenesis are still obscure. Here, we show that WARTS binds via its C-terminus to the PDZ domain of a proapoptotic serine protease Omi / HtrA2. Depletion of WARTS inhibited Omi / HtrA2-mediated cell death, whereas overexpression of WARTS promoted this process. Furthermore, WARTS can enhance the protease activity of Omi / HtrA2 both in vivo and in vitro. Activation of Omi / HtrA2-mediated cell death is thus a potential mechanism for the tumor suppressive activity of WARTS.     

Dopamine D<Subscript>2</Subscript> receptor plays a role in memory function: implications of dopamine–acetylcholine interaction in the ventral hippocampus

Rationale The role of the hippocampal dopaminergic system in mnemonic function has not been clarified yet. Objective We previously reported that the dopamine D₂ receptor (D₂R) is involved in the regulation of acethylcholin (ACh) release in the hippocampus. In this study, we further investigated ACh–dopamine (DA) interaction in the hippocampus and its involvement in mnemonic function. Methods For experiment 1, rats fed with Cholin (Ch)-deficient chow were used. We examined the effects of D₂R antagonist, raclopride, on cognitive performance using a passive avoidance task. We further carried out in vivo microdialysis to assess the effect of infusion of D₂R agonist, quinpirole, into the ventral hippocampus on its capacity to release ACh. For experiment 2, rats fed with normal chow were used. The performance of a radial arm maze task was assessed to examine the effects of hippocampal injection of D₂R agonist, quinpirole, on memory impairment induced by scopolamine, a muscarinic ACh antagonist. Results In experiment 1, rats fed with Ch-deficient chow showed impaired performances indicated by prolonged latency on retention trials of a passive avoidance task following the hippocampal injection of D₂R antagonist, and showed reduced capacity to release ACh following the injection of D₂R agonist compared with rats fed with normal chow. In experiment 2, memory impairment induced by the intraperitoneal injection of scopolamine was ameliorated by the injection of D₂R agonist into the ventral hippocampus. Conclusion These results indicate the possible involvement of hippocampal ACh–DA interaction in mnemonic processing.