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Notes: Abstract: Neuromelanin (NM) is a complex polymer pigment foundprimarily in the dopaminergic neurons of the human substantia nigra. Thestructure of NM is only partially characterized, and its synthesis pathwayremains unknown. We used nuclear magnetic and infrared spectroscopy to examinethe structure of human NM isolated from the substantia nigra compared withsynthetic dopamine melanins. Biochemical analyses were used to investigateproteinaceous and dopaminergic components in these samples. Following acidhydrolysis of NM samples, small amounts of DOPA, dopamine, and a variety ofamino acids were measured. These findings suggest a peptide component in NMstructure. NM also appears to contain a variety of unidentified structuralcomponents possibly derived from the oxidation of dopamine. Human NM differsstructurally from synthetic dopamine melanin, but both human and synthetic NMinclude an aromatic backbone. It is interesting that both human NM andsynthetic melanin also contain a large proportion of aliphatic structures. Ourresults suggest that NM is a more complex pigment than synthetic dopaminemelanin formed via dopamine autoxidation alone.

Notes: 1 We investigated the effects of exogenously applied steroids and endogenously released cortisol on catecholamine (CA) secretion induced by cholinergic agonists in perfused guinea-pig adrenal glands. 2 Acetylcholine (ACh) and electrical stimulation induced CA secretion, which was reversibly inhibited by cortisol. Adrenocorticotropic hormone (ACTH) increased the concentration of cortisol in the perfusion effluent and partly inhibited the secretory response to ACh. 3 Cortisol or aldosterone dose-dependently inhibited secretory responses to nicotine and muscarine. These inhibitory effects were not antagonized by mifepristone and spironolactone, respective cortisol and aldosterone receptor blockers. 4 Dexamethasone, cortisone, corticosterone, 11-deoxycortisol, 11-deoxycorticosterone, prednisolone and cholesterol inhibited nicotine-evoked CA secretion. The secretory response to muscarine was inhibited by these compounds except for dexamethasone and prednisolone. 5 Dexamethasone, cortisol and aldosterone had no effect on CA secretion induced by high KCl. 6 These results suggest that steroids affect nicotinic and muscarinic ACh receptor-mediated responses through distinct mechanisms, and that cortisol released from the adrenal cortex inhibits CA secretion from the adrenal medulla.

Notes: Background There are two chemically distinct types of melanin: the red–yellow phaeomelanin and the brown–black eumelanin. Both types of melanin have been detected in human hair, epidermis and cultured melanocytes.Objectives In a preliminary study, to quantify levels of both eumelanin and phaeomelanin in depigmented as well as repigmented patches of vitiligo following psoralen plus ultraviolet A (PUVA) therapy.Methods We enrolled five patients with vitiligo for this study. We took biopsies from depigmented as well as repigmented lesions after PUVA therapy. The eumelanin and phaeomelanin contents of the skin biopsies were quantified by high-performance liquid chromatography.Results The mean concentrations in depigmented lesions were 229·4 ng per piece for phaeomelanin and 572 ng per piece for eumelanin (mean phaeomelanin/eumelanin ratio 0·36). In repigmented lesions, the mean concentration of phaeomelanin was 74·8 ng per piece and that of eumelanin was 1657·6 ng per piece (mean phaeomelanin/eumelanin ratio 0·049).Conclusions Depigmented lesions showed both types of melanin, and contained a substantial amount of phaeomelanin, whereas repigmented lesions after PUVA showed predominantly eumelanin. We detected melanin in depigmented lesions of vitiligo of 5 years duration, suggesting that some residual melanocytes are still active in depigmented lesions.

Notes: We report a Japanese man with Hermansky–Pudlak syndrome, having oculocutaneous albinism with a bleeding diathesis. Gene analysis of the patient's peripheral blood cells revealed that he was a compound heterozygote for HPS1 gene mutations. One of the mutations was a novel frameshift mutation at codon 321 (a G insertion) in exon 11 (≈ 962–963insG), and the other was a 5′ splice-junction mutation of IVS5 (IVS5 + 5G→A). The content of eumelanin in the patient's hairs was significantly reduced. Histological analysis using light and electron microscopy revealed that melanocytes in the patient's epidermis contained an appreciable number of giant melanosomes. Cultured melanocytes from the patient's skin also contained giant melanosomes. Our finding of mutations in the HPS1 gene in relation to abnormalities in melanosome morphology and melanin production shed light on the role and function of the HPS1 gene product in the synthesis of melanosomes and melanin pigment.

Notes: Background: Proton pump inhibitor triple therapy with clarithromycin and metronidazole has been widely used for Helicobacter pylori eradication. However, the efficacy and the safety of this therapy in patients with liver cirrhosis have not been established. Aim: To evaluate the effect of hepatic dysfunction on metabolism of clarithromycin as it is used for H. pylori eradication therapy in patients with liver cirrhosis, and the efficacy of eradication therapy in those patients. Methods: Serum levels of clarithromycin and its meta-bolite, 14-(R)-hydroxyclarithromycin, were examined in 18 subjects (five normal controls and 13 hospitalized patients with liver cirrhosis) on a selected day between days 7 and 10 of a 2-week course of eradication therapy. This therapy consisted of lansoprazole (30 mg, once a day) together with clarithromycin (200 mg, twice a day) and metronidazole (250 mg, twice a day). In addition, 118 H. pylori-positive out-patients, 88 with peptic ulcer and 30 with liver cirrhosis, underwent the same eradication therapy. Results: Values for the area under the 0–6 h concentration–time curve (AUC) for clarithromycin were not significantly different among the groups. However, the AUC (0–6 h) values of 14-(R)-hydroxyclarithromycin were significantly lower in the Child-Pugh C group than in either the normal controls or the Child-Pugh A/B group. The cure rate for the peptic ulcer patients was 84% on a per protocol analysis (95% CI: 80%−88%) and 81% on an intention-to-treat analysis (95% CI: 77%−85%), while in the liver cirrhosis patients it was 89% in a per protocol analysis (95% CI: 78%−99%) and 83% in an intention-to-treat analysis (95% CI: 70%−97%). Mild adverse effects were observed in 10% of the peptic ulcer patients and 13% of the liver cirrhosis patients, with none leading to premature withdrawal from the study. Conclusion: The 2-week low-dose lansoprazole-based triple therapy tested is a simple, effective and well-tolerated regimen for H. pylori eradication in patients with liver cirrhosis.

Notes: Helicobacter pylori infection is involved in the formation of chronic peptic ulcer. However, a previously reported hypothesis concerning the involvement of central autonomic nervous disorder in this condition cannot be ruled out.〈section xml:id="abs1-2"〉〈title type="main"〉Aim:To use spectrum analysis of heart rate viability to examine autonomic nervous activity before and after H. pylori eradication.〈section xml:id="abs1-3"〉〈title type="main"〉Methods:Twenty patients with chronic duodenal ulcer (duodenal ulcer group) and 20 age-matched normal adults (N group). In both groups, 24-h Holter electrocardiograms (ECGs) were recorded and spectrum analysis of heartrate variability was performed. In the duodenal ulcer group, Holter ECG was recorded before and after H. pylori eradication.〈section xml:id="abs1-4"〉〈title type="main"〉Results:In the N group, analysis of heart rate variability showed that high frequency (HF) power, an index of parasympathetic activity, was high at night, while the low frequency (LF)/HF ratio, an index of sympathetic function, was high during the daytime. In the duodenal ulcer group, HF power was higher at night than during the daytime, showing a similar pattern to the N group, but the power value was higher than in the N group (P 〈 0.05). In the duodenal ulcer group, LF/HF at night was significantly higher than that of the N group. In addition, in the duodenal ulcer group, autonomic activity after H. pylori eradication did not differ significantly from that before H. pylori eradication.〈section xml:id="abs1-5"〉〈title type="main"〉Conclusions:In patients with chronic peptic ulcer, both sympatheticotonia and parasympatheticotonia may occur at night, and this abnormality in autonomic nervous activity may cause increased gastric acid secretion and gastric mucosal vasoconstriction. Abnormalities in autonomic activity persist even after H. pylori eradication, suggesting that they may be an independent risk factor in the formation of chronic peptic ulcer in addition to H. pylori infection.

Notes: Background: The relationship between 1/f fluctuation of the heart rate variability and Helicobacter pylori infection was evaluated, in order to clarify whether autonomic nervous dysfunction is a necessary condition for chronic peptic ulcer formation. Methods: The subjects were 11 patients with recurrent chronic peptic ulcer and 20 age-matched normal subjects. Holter ECGs were recorded over 24 h, and the 1/f –x fluctuation of the heart rate was computed. The 1/f –x fluctuation of the heart rate is a novel index of autonomic function that has been shown to reflect a patient's pleasant mood. For 1/f –x fluctuation, the slope of the regression line (–x) was determined and cosine fitting of the absolute slope of the regression line over a 24-h period was performed. Results: For the normal group, the absolute slope of the regression line during daytime and night-time were 0.53 ± 0.16 and 1.05 ± 0.18, respectively. For the peptic ulcer group, the corresponding values during daytime and night-time were 0.94 ± 0.15 and 1.84 ± 0.18, respectively. The mean value of the cosine curve was 0.76 ± 0.23 in the normal group and 1.12 ± 0.25 in the peptic ulcer group. Thus, these values were significantly higher for the latter group than for the former group (P 〈 0.05). No statistically significant difference in H. pylori infection between the two groups was observed. Conclusions: Autonomic nervous dysfunction as well as H. pylori infection appears to be a necessary condition for chronic peptic ulcer formation.

Notes: Background  Anti-cancer effects of cyclooxygenase (COX)-2 inhibitors have been reported, but not fully investigated in skin and oral diseases. 5-aminolaevulinic acid (ALA)-based photodynamic therapy (PDT) for treating those patients with skin and oral lesions is a highly sophisticated procedure, but the incidence of disease recurrence after treatment is rather significant.Objective  To confirm that COX-2 could be a molecular target in adjunctive therapy to ALA-based PDT, we investigated (i) COX-2 expression in various skin and oral diseases, and (ii) the inhibitory effects on cellular growth of COX-2 selective inhibitor (nimesulide), ALA-based PDT and their combination on human oral squamous cell carcinoma (SCC) cell lines.Methods  A total of 129 biopsy samples from the skin and oral mucosal lesions were tested immunohistochemically for COX-2 expression. Then the in vitro effects of nimesulide, ALA-based PDT, and their combination were determined on two SCC cell lines, HSC-2 and HSC-4. Three different methods (MTT assay, double-staining for annexin V and propidium iodide, caspase-3/CPP32 fluorometric protease assay) were applied for evaluation of their inhibitory effects on these two cell lines.Results  Among the skin diseases, a considerable number of COX-2 high expressers were found in actinic keratosis (15 of 25, 60%), Bowen's disease (13 of 17, 76%) and extramammary Paget's disease (15 of 15, 100%). In contrast, only one of 33 (3%) basal cell carcinoma tumours was a COX-2 high expresser. Among the oral mucosal biopsies, the proportion of COX-2 high expressers increased gradually from hyperplasia (one of six, 17%) through mild dysplasia (five of eight, 63%) and moderate dysplasia (20 of 23, 87%) to severe dysplasia (two of two, 100%). Nimesulide had an inhibitory effect in vitro on HSC-2 (proven to be a COX-2 high expresser), but not on HSC-4 (a COX-2 non-expresser). While ALA-based PDT showed an inhibitory effect on both HSC-2 and HSC-4, most importantly the combination of nimesulide and ALA-based PDT demonstrated a significant synergistic effect on the cellular growth inhibition of only HSC-2, but not of HSC-4.Conclusions  Our study strongly suggests that COX-2 can be one of the molecular targets in treating various skin and oral diseases. The results from our in vitro experiments also prompt us to develop a new protocol with a combination of COX-2 selective inhibitor and ALA-based PDT for more effective treatment of those diseases.

Notes: Background : Nitrates decrease the tone of the lower oesophageal sphincter, and may thus induce gastro-oesophageal reflux.Aim : In the present study, we evaluated electrogastrographic changes and heart-rate variability before and after the administration of nitrates.Methods : In 15 patients with chest pain treated with nitrates, electrocardiography and percutaneous electrogastrography were performed before and after administration of nitrates. Autonomic nervous system function was evaluated by spectral analysis of heart-rate variability and serial changes in low frequency and high frequency power, and the low frequency/high frequency ratio were compared. Electrogastrograms were analysed by obtaining peak power amplitudes and their dominant frequencies.Results : After the administration of nitrates (isosorbide dinitrate), high frequency power, an index of parasympathetic nervous activity, was significantly decreased, whereas the low frequency/high frequency ratio, an index of sympathetic nervous activity, was significantly increased. The mean peak amplitude of the electrogastrogram significantly increased postprandially both before and after treatment. After isosorbide dinitrate treatment, however, mean peak amplitudes after a meal were significantly lower than those obtained before treatment. The mean dominant frequency of the electrogastrogram did not vary before and after treatment.Conclusions : The present study suggests that nitrates inhibit gastrointestinal motility by decreasing autonomic nervous activity.