Kimura's disease: effects of age on clinical presentation.

BACKGROUND: Kimura's disease (KD) is known to be dominant among young Asian men, but it can also occur in middle- and advanced-aged people. The clinical characteristics of KD, especially by age, are not well known. AIM: This study was performed to investigate the effects of age on the clinical characteristics of KD. DESIGN: We conducted a case series study. METHODS: All case studies of patients diagnosed with KD were collected via a PubMed search of studies published until August 2018. The data were analyzed by age group. RESULTS: In total, 215 studies were reviewed (238 patients; mean age of 36 years). The male:female ratio was 4:1 overall, 17:1 in patients aged <20 years, 4:1 in patients aged 20-39 years and 2:1 in patients aged ≥40 years (P = 0.01). The percentage of patients with pruritus was 15.4% overall, 3.8% in patients aged <20 years, 15.5% in patients aged 20-39 years and 21.7% in patients aged ≥40 years (P = 0.02). The time to diagnosis was 5.3 years overall, 3.2 years in patients aged <20 years, 4.7 years in patients aged 20-39 years and 7.1 years in patients aged ≥40 years (P < 0.01). CONCLUSIONS: The proportion of female patients affected the incidence of pruritus, and the time to diagnosis increased as the patients' age increased. There were no significant age-related differences in region/race, complications, multiplicity, laterality, anatomical distribution, maximum size, eosinophil count, immunoglobulin E level, initial treatment, recurrence or outcomes. This may be useful information for the diagnosis of KD.

Deep-learning-based, computer-aided classifier developed with a small dataset of clinical images surpasses board-certified dermatologists in skin tumour diagnosis.

BACKGROUND: Application of deep-learning technology to skin cancer classification can potentially improve the sensitivity and specificity of skin cancer screening, but the number of training images required for such a system is thought to be extremely large. OBJECTIVES: To determine whether deep-learning technology could be used to develop an efficient skin cancer classification system with a relatively small dataset of clinical images. METHODS: A deep convolutional neural network (DCNN) was trained using a dataset of 4867 clinical images obtained from 1842 patients diagnosed with skin tumours at the University of Tsukuba Hospital from 2003 to 2016. The images consisted of 14 diagnoses, including both malignant and benign conditions. Its performance was tested against 13 board-certified dermatologists and nine dermatology trainees. RESULTS: The overall classification accuracy of the trained DCNN was 76·5%. The DCNN achieved 96·3% sensitivity (correctly classified malignant as malignant) and 89·5% specificity (correctly classified benign as benign). Although the accuracy of malignant or benign classification by the board-certified dermatologists was statistically higher than that of the dermatology trainees (85·3% ± 3·7% and 74·4% ± 6·8%, P < 0·01), the DCNN achieved even greater accuracy, as high as 92·4% ± 2·1% (P < 0·001). CONCLUSIONS: We have developed an efficient skin tumour classifier using a DCNN trained on a relatively small dataset. The DCNN classified images of skin tumours more accurately than board-certified dermatologists. Collectively, the current system may have capabilities for screening purposes in general medical practice, particularly because it requires only a single clinical image for classification.

Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults.

Cardiomyocyte death following ischaemic/hypoxic injury causes irreversible damage to cardiac function and contributes to chronic diseases such as heart failure. Understanding the mechanisms associated with myocyte loss under these conditions can help to identify strategies to minimise/abrogate such detrimental effects. The p53 protein can induce apoptosis or cell cycle arrest, but effects on cell fate depend on interactions with other regulators such as POU4F2/Brn-3b (Brn-3b), which co-operates with p53 to increase the expression of pro-apoptotic genes. In contrast, the related POU4F1/Brn-3a (Brn-3a) blocks p53-mediated apoptosis but co-operates with p53 to enhance cell cycle arrest. In this study, we showed that permanent coronary artery ligation in mouse hearts, which induced apoptotic markers, activated caspase-3 and -8 and necroptosis markers; RIP-1 and -3 also increased Brn-3b and Brn-3a expression. However, Brn-3a was only detected in uninjured myocardium but not at the site of injury, whereas Brn-3b showed generalised increase, including within the infarct zone. Conversely, p53 was detected in the infarct zone and in some cells adjacent to the site of injury but not in uninjured myocardium. Co-localisation studies showed Brn-3a co-expression with p53 in cardiomyocytes adjacent to the infarct zone, whereas Brn-3b was co-localised with p53 in the infarct zone only. Increased Brn-3b and p53 correlated with elevated expression of pro-apoptotic target genes, Bax, Noxa and PUMA, whereas cleaved caspase-3 confirmed the presence of apoptotic cells within this region of the injured heart. Similarly, simulated ischaemia/reoxygenation (sI/R) injury in neonatal rat ventricular cardiomyocytes (NRVM) and heart derived H9c2 myoblasts increased Brn-3b, p53 as well as apoptotic genes, and this was associated with enhanced apoptosis. Furthermore, targeted reduction of Brn-3b using shRNA caused reduction in pro-apoptotic Bax and Noxa proteins, even though p53 expression remained intact, suggesting that Brn-3b is important for controlling the fate of the myocardium in the injured heart.

Estudio fitoquímico y farmacológico de 4 Plantas con efecto hipoglicemiante / Phytochemical and pharmacological studies in four plants with hypoglycemic effect

Se realizó el estudio de la acción hipoglicemiante de Ocimum sanctus (Albahaca morada), Notholaena nivea (Cuti-Cuti), Geranuim lechleri (Pasuchaca) y Smallantus sonchifolius (Yacón), frente a la hiperglicemia aloxánica, tanto de los extractos atomizados, como del pool de alcaloides, de cada una de las plantas. Igualmente, se determinó la DL50 del extracto atomizado y de los alcaloides de las cuatro plantas evaluadas. La toxicidad aguda se determinó en ratones albinos, cepa nihs, cuyos pesos oscilaron entre 25 y 30 g. La acción hipoglicemiante, fue evaluada en ratas albinas cepa holtzman, de 200 a 250 g de peso. Tanto los extractos atomizados, como los alcaloides de Cuti-Cuti, Pasuchaca y hojas de Yacón, mostraron un excelente efecto hipoglicemiante, frente a la hiperglicemia inducida por aloxano. Las tres plantas poseen escasa toxicidad aguda, y según los criterios de Williams podrían considerarse como plantas prácticamente atóxicas. Sin embargo, solamente el pool de alcaloides de Albahaca a la dosis de 250 mg/ kg de peso, mostró una escasa acción hipoglicemiante, no mostrando eficacia la dosis de 500mg/kg, del pool de alcaloides, ni el atomizado de la planta, a la dosis de 1000 mg/kg de peso.

The study of the hypoglicemic action of Ocimum sanctum (Albahaca morada), Notholaena nivea (Cuti-Cuti), Geranuim lechleri (Pasuchaca) and Smallantus sonchifolius (Yacón), was performed on alloxan-induced hyperglicemic rats. In addition, atomized extracts and the pool of alkaloids, of the different plants were studied. To evaluate acute toxicity, DL50 of the atomized extract and of the alkaloids on the four plants were determined using albino mice, whose weights oscillated between 25 and 30 g. The hypoglycemic action, was evaluated in Holtzman albino rats, of 200 to 250 g of weight. The atomized extracts, as well as the alkaloids of Cuti-Cuti, Pasuchaca and leaves of Yacón, showed an excellent hypoglicemic effect in the hyperglicemic alloxaninduced rats. These three plants have little acute toxicity and according to the Williams` criteria they could be considered as practically non toxic. On the other hand only the pool of alkaloids of Albahaca, at the dose of 250 mg/kg showed little hypoglicemic action. No hypoglicemic effect was observed with the albahaca alkaloids at the dose of 500mg/kg nor with the atomized extract of the plant at the dose of 1000 mg/kg.

Protein kinase C-mediated cell death mode switch induced by high glucose.

Cortical neurons rapidly die in necrosis due to poor glucose uptake in the low-density (LD) culture under serum-free condition without any supplements. The scanning and transmission electron microscopical analyses characterized the necrosis by membrane disruption, mitochondrial swelling and loss of cytoplasmic electron density. High-glucose treatment delayed the neuronal death by suppressing necrosis, but induced apoptosis through increase in Bax levels, cytochrome c release, caspase-3 activation and DNA ladder formation. Although pyruvate as well as high glucose inhibited necrotic cell death and rapid decrease in cellular ATP levels, possibly related to decreased [(3)H]-2-deoxy glucose uptake under the serum-free condition, it did not induce apoptosis. Protein kinase C inhibitors blocked these changes related to the cell death mode switch. Several neurotrophic factors did not affect the necrosis, but potentiated high-glucose-induced survival activity, while inhibiting cytochrome c release. All these results suggest that high-glucose treatment causes neuronal cell death mode switch by inhibiting necrosis, while inducing apoptosis, which is prevented by neurotrophic factors.

Protein kinase C-mediated necrosis-apoptosis switch of cortical neurons by conditioned medium factors secreted under the serum-free stress.

Cortical neurons die in necrosis in the low-density (LD) culture, and in apoptosis in the high-density (HD) culture under the serum-free condition without any supplements. The neuronal death in LD culture was delayed by conditioned medium (CM) factors prepared from the HD culture. The CM switched the cell death mode from necrosis to apoptosis, characterized by various cell death markers and transmission electron microscopy. The CM inhibited the rapid decrease in cellular ATP levels and [3H]-2-deoxy glucose ([3H]-2-DG) uptake in the LD culture. Inhibitors of phospholipase C and protein kinase C effectively abolished the CM-induced elevation of survival activity, [3H]-2-DG uptake and ATP levels, and necrosis-apoptosis switch. All these results suggest that CM caused the cell death mode switch from necrosis to apoptosis through phospholipase C- and protein kinase C-mediated mechanisms.

Circumvention of acquired resistance to doxorubicin in K562 human leukemia cells by oxatomide.

We studied the effect of oxatomide, an antiallergic drug, on the resistance of K562 cells to doxorubicin. Oxatomide synergistically potentiated the cytotoxicity of doxorubicin in doxorubicin-resistant K562 cells (K562/DXR) at a concentration of 1-10 microM, but had hardly any synergistic effect on the parental cell line (K562) at the same concentration. Oxatomide inhibit P-glycoprotein pump-efflux activity and the binding of [3H]-azidopine to the cell-surface protein P-glycoprotein, in a dose-related manner. These results indicate that oxatomide reverses the multidrug-resistance phenotype through direct interaction with P-glycoprotein.

ATP suppresses the K(+) current responses to FSH and adenosine in the follicular cells of Xenopus oocyte.

The application of either follicle-stimulating hormone (FSH) or adenosine (Ade) induces a K(+)-current response in the follicular cells surrounding a Xenopus oocyte under a voltage clamp. These K(+)-current responses are reported to be produced by an increase in intracellular cAMP. A previous application of ATP to the same cells markedly depressed the K(+)-current responses to FSH and Ade. Furthermore, a 2 min application of phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC), significantly depressed the K(+)-current responses to FSH and Ade, but it had no significant effect on the Cl(-)-current response to ATP. An application of either ATP or PDBu also depressed the K(+)-current response induced by intracellularly applied cAMP. In contrast to the effect of PDBu, the application of 1-octanol, an inhibitor of gap junction channel, significantly depressed both the Ade- and ATP-induced responses, indicating that the acting site of 1-octanol is different from that of PKC. The results suggest that the depressing effect of ATP on the FSH- and Ade-induced K(+)-current responses might be mediated by PKC activation and that the site of PKC action might be downstream of the cAMP production involved in the K(+) channel opening.

Diels-Alder reaction of 1,3-butadiene derivatives with 1-methyl-2(1H)-quinolones having an electron-withdrawing group at the 4-position.

Diels-Alder reactions of 1-methyl-2(1H)-quinolones having an electron-withdrawing group at the 4-position with isoprene, butadiene sulfone, and cyclohexadiene were performed to yield functionalized phenanthridones stereoselectively at atmospheric and at high pressure. Regioselectivity and stereochemistry of a methoxycarbonyl group were studied using the semi-empirical and ab initio MO methods, respectively.

Reversal of vinblastine resistance in human leukemic cells by haloperidol and dihydrohaloperidol.

Haloperidol, an antipsychotic, was investigated in cells overexpressing P-glycoprotein to detemine whether it was a clinically effective drug to reverse for reversing multidrug resistance (MDR) mediated by P-glycoprotein. A nontoxic concentration of haloperidol (1-30 microM) enhanced the cytotoxic effects of vinblastine (VBL) concentration-dependently in VBL-resistant human leukemia (K562/VBL) cells, but had no effect in the parent cells. Haloperidol also enhanced the cytotoxicities of epirubicin, doxorubicin and actinomycin D in the K562/VBL cells, but not those of idarubicin or cisplatin; this enhancement was less than that of the VBL toxicity in the VBL-resistant tumor line. Haloperidol increased the intracellular accumulation of VBL in the K562/VBL cells, and the binding of [3H]-azidopine to the cell-surface protein, P-glycoprotein, was inhibited by haloperidol in a concentration-dependent manner. Haloperidol was less potent than verapamil. Thus, haloperidol appeared to potentiate anticancer agents through the reversal of MDR by competitively inhibiting drug-binding to P-glycoprotein. In contrast, the main metabolite of haloperidol, dihydrohaloperidol, without antipsychotic activity, had less of an effect. Therefore, haloperidol might be useful in reversing drug-resistance.

Diels-Alder reactions of nitro-2(1H)-pyridones with 2,3-dimethyl-1,3-butadiene.

Diels-Alder (DA) reactions of 3- or 5-nitro-2(1H)-pyridones and nitro-2(1H)-pyridones containing a methoxycarbonyl group with 2,3-dimethyl-1,3-butadiene were examined. The DA reactions of 3-nitro-2(1H)-pyridones in this paper represent, to the best of our knowledge, the first report of DA reactions of 3-substituted 2(1H)-pyridones and consequent production of isoquinolones. Performing the same reactions with 5-nitro-2(1H)-pyridones yielded quinolones. DA reactions of 2(1H)-pyridones with nitro and methoxycarbonyl groups produced isoquinolones, quinolones and phenanthridones (the double DA adducts), aromatized or hydrogenated. The substituent effect was evaluated by calculating the activation energy, using the ab initio MO method.

Cycloaddition of 2(1H)-pyridones having a methoxycarbonyl group to 1,3-butadiene derivatives.

The cycloaddition of 4-methoxycarbonyl-2(1H)-pyridones to silyloxydienes gave isoquinolone derivatives in reasonable yields. Furthermore, the cycloaddition of 6-methoxycarbonyl-2(1H)-pyridones to 2,3-dimethyl-1,3-butadiene produced cycloadducts (isoquinolone and quinolone derivatives) and double cycloadducts (phenanthridone derivatives). The activation energies using Gaussian 98 with RHF/3-21G level of 4- and 6-methoxycarbonyl-2(1H)-pyridones coincided with the experimental facts.

Synthesis of isoquinoline derivatives by Diels-Alder reactions of 2(1H)-pyridones having an electron-withdrawing group with methoxy-1,3-butadienes.

Diels-Alder (DA) reactions of 2(1H)-pyridones having an electron-withdrawing group at the 4-position with 2,3-dimethoxy- and 2-methoxy-1,3-butadienes gave isoquinoline derivatives. Furthermore, an isoquinoline alkaloid (6,7-dimethoxy-2-methyl-1(2H)-isoquinolone) was synthesized by elimination of hydrogen cyanide and dehydrogenation of the DA-adduct having a cyano group at the 4a-position.

Enhancement of doxorubicin activity in multidrug-resistant cells by mefloquine.

We studied the effect of the antimalarial drug mefloquine on the resistance of K562 cells to doxorubicin. Mefloquine synergistically potentiated the cytotoxicity of doxorubicin for doxorubicin-resistant K562 cells (K562/DXR) at a concentration of 0.5-3 microM, but had hardly any synergistic effect in the parental cell line (K562) at the same concentration. Mefloquine was more potent than verapamil, a known modulator of multidrug-resistance. Since doxorubicin resistance in these cells is associated with the expression of high levels of P-glycoprotein, we evaluated the effect of mefloquine and of P-glycoprotein activity in cytofluorographic efflux experiments with the fluorescent dye rhodamine 123. Our results indicate that mefloquine inhibits the P-glycoprotein pump-efflux activity in a dose-related manner. Moreover, mefloquine reduces the expression of the immunoreactive P-glycoprotein in K562/DXR cells as evaluated by cytofluorimetric assay. Taken together, the results indicate that mefloquine reverses the multidrug-resistance phenotype through direct interaction with P-glycoprotein.

Heterodimerization of Bcl-2 and Bcl-X(L) with Bax and Bad in colorectal cancer.

The rate of cell loss owing to apoptosis is mediated by competitive dimerization with selective pairs of cell death antagonists (Bcl-2, Bcl-X(L)) and agonists (Bax, Bad). The aim of this study was to investigate which Bcl-2 family dimers had a critical factor in colorectal cancer. We analyzed the expression of Bcl-2, Bcl-X(L), Bax, and Bad in normal-appearing mucosa and colorectal tumor tissues by Western blotting after immunoprecipitation. Compared with the ratio of Bax-Bcl-2/total Bax in normal mucosa, the ratio was significantly reduced in tumors (p = 0.02). In this series, the low ratio of Bad-Bcl-2/total Bcl-2 was associated with advanced tumor stages (p = 0.02). A reduced heterodimerization of Bax with Bcl-2 may contribute to the development of colorectal cancer. The heterodimerization of Bad with Bcl-2 may be repressed in advanced tumor tissues, and may contribute to tumor growth in colorectal cancer.

Reversal of multidrug resistance in human leukemia K562 by tamolarizine, a novel calcium antagonist.

A new type of organic Ca2+ channel blocker, tamolarizine, was examined for its reversing effect on multidrug-resistant tumor cells. Tamolarizine synergistically potentiated the cytotoxicity of doxorubicin for doxorubicin-resistant K562 cells (K562/DXR) at a concentration of 0.1-10 microM, but had hardly any synergistic effects in the parental cell line (K562) at the same concentration. Moreover, tamolarizine inhibits the P-glycoprotein pump-efflux activity in a dose-related manner and reduces the expression of the immunoreactive P-glycoprotein in K562/DXR cells as evaluated by cytofluorimetric assay. These results indicate that tamolarizine reverses the multidrug-resistance phenotype through direct interaction with P-glycoprotein.

Colonoscopic polypectomy with cutting current: is it safe?

BACKGROUND: Coagulation and blended electrosurgical current are currently recommended for colonoscopic polypectomy, whereas pure cut current is believed to be associated with a higher risk of bleeding. However, the outcome of polypectomy performed with a cut current has not been evaluated in a large case series. Our objective was to study the incidence and nature of complications when polypectomy is performed with a pure cut current. METHODS: Among 9555 colonoscopic examinations, polypectomy cases were retrospectively reviewed for complications. The electrosurgical current applied was always the cutting waveform. RESULTS: Electrosurgical polypectomy using pure cut current was performed to remove 4735 lesions. Hemoclips were applied to the excision site after polypectomy to prevent bleeding in 12% of the cases. Hemorrhage occurred in 1.1% of the polypectomies (3.1% of patients). The incidence of bleeding with the different methods was snare polypectomy 0.9%, endoscopic mucosal resection 1.6%, "hot" biopsy 0.4%, and piecemeal polypectomy 7.3%. Bleeding was immediate in 66.1% of episodes and delayed in 33.9%. Patients with delayed postpolypectomy bleeding were significantly younger than those with immediate bleeding (50.5 and 64.7 years, respectively, p < 0.001). There was 1 case of transmural burn, but no perforations. CONCLUSION: Polypectomy can be performed with pure cut current with a bleeding rate comparable to that seen with the use of coagulation or blended current, provided that hemoclip placement can be used readily. Expertise in hemoclip placement is advisable if this method of polypectomy is to be used.