Multiple skin cancers in patients with mycosis fungoides after long-term ultraviolet phototherapy.

Phototherapy is a useful noninvasive therapy, but it can induce cutaneous malignant tumours, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). We report on a 79-year-old man who had long-standing mycosis fungoides for 40 years, which had been treated with psoralen ultraviolet A therapy for 37 years at a dose of approximately 5000 J/cm2 . Approximately 6 years before presentation, numerous types of cutaneous malignancies, including actinic keratosis, BCC and SCC, had begun to develop all over the patient's body. We hypothesized that he was experiencing a pathogenesis similar to patients with xeroderma pigmentosum (XP), and we therefore assessed his DNA repair capacity. Based on these investigations, the patient was eventually diagnosed as non-XP, even though we detected that his DNA repair capacity was slightly lower than that of normal controls, which may have led to the skin cancers. We speculate that multiple skin malignancies can be induced by long-term phototherapy in patients with slightly impaired DNA repair capacity.

Transgenic mice overexpressing nesfatin/nucleobindin-2 are susceptible to high-fat diet-induced obesity.

BACKGROUND: Nesfatin/Nucleobindin-2 (Nesf/NUCB2), a precursor of nesfatin-1, an anorexigenic protein, is ubiquitously expressed in peripheral tissues in addition to the hypothalamus. However, the role of intracellular Nesf/NUCB2 has not been established in the periphery. METHODS: Nesf/NUCB2-transgenic (Tg) mice were generated, and chronological changes of body weight and daily food intake were measured in Nesf/NUCB2-Tg mice fed normal laboratory chow or 45% high-fat diet (HFD). In addition, changes of metabolic markers were evaluated in those mice. RESULTS: No differences were observed in daily food intake and body weight between Nesf/NUCB2-Tg mice (n=11) and their non-Tg littermates (n=11) fed normal chow. Nesf/NUCB2-Tg mice showed increased mRNA expression of oxytocin and corticotropin-releasing hormone and decreased mRNA expression of cocaine- and amphetamine-related transcript in the hypothalamus. Nesf/NUCB2-Tg mice fed 45% HFD (n=6) showed significantly higher increase in body weight than their non-Tg littermates fed the same diet (n=8); however, no difference was observed in daily food intake between these two groups. Further, Nesf/NUCB2-Tg mice fed 45% HFD showed a significant increase in the weight of the liver, subcutaneous fat, and brown adipose tissue and decrease in the expression of uncoupling protein-1 in the subcutaneous fat. Blood glucose levels of Nesf/NUCB2-Tg mice fed 45% HFD were not different from those of their non-Tg littermates fed the same diet. Insulin levels of these Tg mice were significantly higher than those of their non-Tg littermates. Histological analysis showed marked fat deposition in the hepatocytes surrounding the hepatic central veins in Nesf/NUCB2-Tg mice fed 45% HFD. CONCLUSIONS: Overexpression of Nesf/NUCB2 did not change food intake, but increased body weight only in Nesf/NUCB2-Tg mice fed HFD. The results of this study indicate that Nesf/NUCB2 was involved in the development of insulin resistance and fat deposition in the liver, independent of the modulation of energy intake.

Variation of radiocesium concentrations in cedar pollen in the Okutama area since the Fukushima Daiichi Nuclear Power Plant accident.

Due to releases of radionuclides in the Fukushima Daiichi Nuclear Power Plant accident, radiocesium ((134)Cs and (137)Cs) has been incorporated into large varieties of plant species and soil types. There is a possibility that radiocesium taken into plants is being diffused by pollen. Radiocesium concentrations in cedar pollen have been measured in Ome City, located in the Okutama area of metropolitan Tokyo, for the past 3 y. In this research, the variation of radiocesium concentrations was analysed by comparing data from 2011 to 2014. Air dose rates at 1 m above the ground surface in Ome City from 2011 to 2014 showed no significant difference. Concentration of (137)Cs contained in the cedar pollen in 2012 was about half that in 2011. Between 2012 and 2014, the concentration decreased by approximately one-fifth, which was similar to the result of a press release distributed by the Japanese Ministry of Agriculture, Forestry and Fisheries.

Laparoscopic gastric electrical stimulation for medically refractory diabetic and idiopathic gastroparesis.

BACKGROUND: Gastric electrical stimulator (GES) implantation is effective in certain patients with gastroparesis; however, laparotomy is often employed for placement. The aim of this study is to review outcomes of patients who underwent laparoscopic GES therapy for diabetic and idiopathic gastroparesis at a large referral center. METHODS: Patients who underwent GES (Enterra Therapy System; Medtronic, Minneapolis, MN) implantation with subsequent interrogation and programming between March 2001 and November 2011 were analyzed. RESULTS: A total of 113 patients underwent GES placement or revision during the study period. One hundred eleven patients underwent primary GES at our institution, while two patients underwent GES generator revision at our institution. Primary operations were completed laparoscopically in 110 of 111 cases, with one conversion to laparotomy due to severe adhesions. At a mean follow-up of 27 months (1-113), symptom improvement was achieved in 91 patients (80 %) and was similar for both the diabetic and idiopathic subgroups. Need for supplemental nutrition (enteral and/or parental) decreased in both groups. CONCLUSIONS: GES placement is feasible using a laparoscopic approach. Medical refractory gastroparesis in the diabetic and idiopathic groups had significant symptom improvement with no difference between the two groups. Need for supplemental nutrition is decreased following GES.

Effect of a fermented nutraceutical on thioredoxin level and TNF-alpha signalling in cirrhotic patients.

The aim of this study is to gain further insights into the possible nutraceutical effect on redox balance via thioredoxin (Trx) modulation and on the intrinsic susceptibility of monocytes to generate an inflammatory response. The study group consisted of thirty-two patients with compensated Child A-C, HCV-related cirrhosis. The patients were supplemented for 6 months with 6g/day of a certified fermented papaya preparation (FPP). Fifteen unsupplemented, age/gender-matched healthy subjects served as controls. The patients filled in a detailed diet-life style questionnaire, and blood samples were collected to test routine biochemistry, Trx, redox status (GSH, GSSG, GSH/GSSG ratio, 4-HNE and alpha-tocopherol). Moreover, isolated monocytes were tested for ex-vivo LPS-stimulated TNF-alpha production and TNF-alpha mRNA. As compared to control, patients with liver cirrhosis showed a significantly higher serum level of Trx. A significant correlation occurred with GSH/GSSG ratio in Child B and C patients. FPP supplementation brought about a significant reduction of Trx with levels comparable to the ones of healthy controls. Ten patients Child C (31.2 percent) showed borderline low levels of alpha-tocopherol while all cirrhotic patients, as a whole, showed a significantly abnormal redox balance. Supplementation with FPP did not modify alpha-tocopherol depletion but significantly improved redox balance parameters. Patients with liver cirrhosis showed a significantly upregulated TNF-alpha production in a time-dependent manner and this effect was more pronounced in more advanced stages of the disease and showed a significant correlation with alpha-tocopherol level. Supplementation with FPP significantly, although partially, downregulated TNF-alpha production from monocytes. Taken altogether, it would appear that the typical oxidative-inflammatory biochemical milieu of these patients is mirrored by a significant TNF-alpha upregulation at a monocyte level while a targeted nutraceutical might be a potentially amenable intervention to be part of validated scheduled treatments.

Effect of volitional relaxation and motor imagery on F wave and MEP: do these tasks affect excitability of the spinal or cortical motor neurons?

OBJECTIVE: To test if simple motor imagery, like thumb abduction, preferentially influences the excitability of the spinal or cortical motoneurons. METHODS: Ten healthy subjects underwent two separate experiments, each consisting of recording F waves and MEPs from abductor pollicis brevis (APB) in three consecutive sessions: (1) baseline, (2) after immobilizing APB for 3 h, and (3) after brief muscle exercise. During the immobilization, the subjects were instructed to volitionally relax APB in experiment 1 (relaxation task), and mentally simulate thumb abduction without actual movement in experiment 2 (imagery task). RESULTS: Relaxation task suppressed both MEPs and F waves. Motor imagery reduced this suppression, restoring F waves nearly completely (94%) and MEPs only partially (77%). Hence, the rest-induced decline of MEPs in part results from cortical modulation. In contrast, statistical analysis revealed no differences in imagery-induced recovery of motoneuron excitabilities whether assessed by F wave or MEP. Thus, increased excitability of spinal motoneurons responsible for F-wave changes also accounts for recovery of MEPs. CONCLUSIONS: Volitional relaxation depresses the spinal and cortical motoneurons, whereas mental simulation counters rest-induced suppression primarily by restoring spinal excitability. SIGNIFICANCE: The present findings help elucidate physiologic mechanisms underlying motor imagery.

The satiety molecule nesfatin-1 is co-expressed with melanin concentrating hormone in tuberal hypothalamic neurons of the rat.

Overlapped in the tuberal hypothalamic area (THA), melanin-concentrating hormone (MCH) and hypocretin (Hcrt) neurons contribute to the integrated regulation of food intake, energy regulation and sleep. Recently, physiological role in appetite suppression has been defined for a novel hypothalamic molecule, nesfatin-1. Acute i.c.v. infusion of nesfatin-1 (nesf-1) promotes anorexia whereas chronic treatment reduces body weight in rats. This satiety molecule is expressed in neurons from areas prominently involved in appetite regulation including THA. We therefore sought functionally relevant to determine whether nesf-1 might be a reliable signaling marker for a new cell contingent within THA, in addition to MCH and Hcrt neurons. Thus, we completed a detailed topographical mapping of neurons immunostained for nesf-1 (nesf-1+) together with cell quantification in each discrete nucleus from THA in the rat. We further combined the immunodetection of nesf-1 with that of MCH or Hcrt to assess possible co-expression. More than three quarters of the nesf-1+ neurons were encountered in nuclei from the lateral half of THA. By double immunofluorescent staining, we showed that all neurons immunoreactive for melanin concentrating hormone (MCH+) neurons depicted nesf-1 immunoreactivity and approximately 80% of the nesf-1+ neurons were labeled for MCH. Maximal co-expression rates were observed in the lateral THA containing approximately 86% of the double-labeled neurons plotted in THA. The present data suggest that nesf-1 co-expressed in MCH neurons may play a complex role not only in food intake regulation but also in other essential integrative brain functions involving MCH signaling, ranging from autonomic regulation, stress, mood, cognition to sleep.

Effect of motion imagery to counter rest-induced suppression of F-wave as a measure of anterior horn cell excitability.

OBJECTIVE: To test if motor imagery prevents the rest-induced suppression of anterior horn cell excitability. METHODS: Ten healthy subjects underwent two separate experiments, each consisting of stimulating the median nerve 100 times and recording F-waves from abductor pollicis brevis (APB) in three consecutive sessions: (1) after muscle exercise to standardize the baseline, (2) after immobilization of APB for 3h and (3) after muscle exercise to check recovery. We instructed the subject to volitionally relax APB in experiment 1 (relaxation task), and to periodically simulate thumb abduction without actual movement in experiment 2 (imagery task). RESULTS: F-wave persistence and amplitude declined after relaxation task and recovered quickly after exercise, but changed little with imagery task. F-wave latencies showed no change when analyzed individually. The frequency distribution of collective F-waves recorded from all subjects remained the same after relaxation task, but showed a shift toward longer latencies after imagery task. CONCLUSIONS: Mental imagery without overt motor output suffices to counter the effect of sustained volitional muscle relaxation, which would, otherwise, cause a reversible reduction in anterior horn cell excitability. SIGNIFICANCE: This finding documents the importance of central drive for spinal excitability, which affects F-wave studies of a paretic muscle.

Nutraceutical strategy in aging: targeting heat shock protein and inflammatory profile through understanding interleukin-6 polymorphism.

The aging process is paralleled by two- to fourfold increases in plasma/serum levels of inflammatory mediators, such as cytokines and acute-phase proteins. In this study we assessed the inflammatory profile and polymorphism of healthy elderly subjects and the influence of a nutraceutical supplement. Forty elderly, generally healthy subjects were recruited, divided into two matched groups, and given either a fermented papaya preparation 9 g/day by mouth or the same amount of placebo. Treatments were carried out in a cross-over manner with a 3-month supplementation period followed by a 6-week washout period between treatments. Ten healthy young subjects served as controls. Interleukin-6 (IL-6) promoter -174 G/C polymorphism genotype was determined together with blood levels for redox status, proinflammatory cytokines, high sensitivity C-reactive protein, and serum 70 kDa heat shock protein (Hsp70) concentrations. Tumor necrosis factor-alpha and IL-6 were higher in elderly subjects (P < 0.05 versus young controls). The concentration of Hsp70 inversely correlated with markers of inflammation in -174 G/C-negative subjects (r = 0.62, P < 0.05). Nutraceutical intervention normalized the inflammatory parameters (P < 0.05) with a rise of Hsp70 (P < 0.05). This suggests that healthy elderly individuals may have a proinflammatory profile playing as a downregulating factor for inducible Hsp70, particularly if -174 G/C-negative. A nutraceutical intervention seems able to beneficially modulate such a phenomenon.

Auditory brainstem response findings and peripheral auditory sensitivity in adrenoleukodystrophy.

Measurements of the auditory brainstem response (ABR) were obtained in 96 individuals with X-linked adrenoleukodystrophy (X-ALD). The patients were divided into five diagnostic groups on the basis of neurologic diagnosis. The five groups were cerebral childhood and adolescent, pure adrenomyeloneuropathy (pure AMN), adrenomyeloneuropathy cerebral (AMN cerebral), Addison's only and symptomatic female heterozygotes. Results indicated the presence of marked ABR abnormalities for all groups most frequently involving Wave V, followed by Wave III and Wave I. Abnormalities of all interpeak latency intervals (i.e., I-III, III-V and I-V) were observed for all groups. ABR abnormalities were most frequently seen in the AMN-cerebral and pure AMN groups but were also common in the symptomatic female heterozygote group. The ABRs in the cerebral childhood and adolescent group were the least impaired of the five groups examined. Age was found to be a significant independent predictor of bilateral ABR abnormalities but VLCFA levels, MRI Loes score, and duration of symptoms were not found to be independent predictors of bilateral ABR abnormalities after adjusting for ALD phenotype. Patients with AMN were significantly more likely to have bilateral ABR abnormalities than the cerebral childhood and adolescent group after adjusting for age, duration of symptoms, EDSS score, VLCFA levels and MRI Loes scores. The prevalence of peripheral hearing loss was not found to exceed that present in age and sex matched normal control groups derived from the NHANES (1999-2000), indicating a lack of association between peripheral hearing loss and X-linked adrenoleukodystrophy. It was concluded that: (1) auditory sensitivity in X-ALD is not significantly impaired; (2) ABR abnormalities are a frequent finding and may be caused by abnormalities of fiber tracts in the region of the lateral lemniscus and inferior colliculus; and, (3) the abnormalities progress slowly and appear to be associated mainly with the AMN phenotype.

Antibacterial properties of a new isoflavonoid from Erythrina poeppigiana against methicillin-resistant Staphylococcus aureus.

A new isoflavonoid, together with four known isoflavonoids, was isolated from the roots of Erythrina poeppigiana. The chemical structure was determined by extensive spectroscopic studies, and then its antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) was investigated. The new isoflavonoid was identified as 3,9-dihyroxy-10-gamma,gamma-dimethylallyl-6a,11a-dehydropterocarpan (compound 1). Compound 1 inhibited bacterial growth most potently of the five isolates, and had a minimum inhibitory concentration (MIC) of 125 microg/ml against thirteen MRSA strains. Inhibitory activity was based on bactericidal action and viable cell number reduced by approximately 1/10,000 after 4 h incubation with compound 1. Despite intense bactericidal action against MRSA, compound 1 never resulted in leakage of 260 nm-absorbing substances from bacterial cells. Compound 1 (12.5 microg/ml) completely inhibited incorporation of radio-labeled thymidine, uridine and leucine into MRSA cells. Although glucose incorporation was also markedly inhibited by the compound, the amount of glucose incorporated by bacterial cells increased gradually with incubation time. These findings suggest that compound 1 exhibits anti-MRSA activity by interfering with incorporation of metabolites and nutrients into bacterial cells or by affecting the nucleic acids of MRSA cells. Furthermore, this new compound could be a potent phytotherapeutic agent for treating MRSA infections.

Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action.

BACKGROUND: H1-receptor antagonists are often effective in the treatment of allergic disorders such as atopic dermatitis. Cetirizine, a putative H1-receptor antagonist, has recently been shown to have anti-inflammatory properties through the inhibition of leucocyte recruitment and activation, and by the reduction of ICAM-1 expression on keratinocytes. OBJECTIVE: To further elucidate the anti-inflammatory properties of cetirizine, we first examined its effects on antigen-induced eosinophilia and neutrophila in vivo. We then examined the anti-inflammatory effects of cetirizine on a human keratinocyte A431cell line. METHODS: Mice were sensitized subcutaneously with ragweed pollen and were challenged intraperitoneally with the allergen. Cetirizine diluted in sterile water (0-20 mg/kg) or only sterile water was administered orally. Peritoneal cells were obtained at 8 and 24 h after challenge. The eosinophilia and neutrophilia induced by ragweed pollen extract were quantitated. Macrophage migration inhibitory factor (MIF), macrophage inflammatory protein 2 (MIP-2) and eotaxin contents of peritoneal fluid were also measured by mouse ELISA. The effects of cetirizine on MIF-induced IL-8 production in A431 cells were examined by ELISA. The effects of cetirizine on MIF expression and production in A431 cells were examined by human MIF ELISA and Northern blot analysis. RESULTS: Eosinophilia and neutrophilia induced by ragweed pollen extract were found to be significantly reduced in cetirizine-treated mice (20 mg/kg). MIF, a pleuripotent cytokine, was significantly decreased at 8 and 24 h in the peritoneal fluid by cetirizine treatment. MIP-2 and eotaxin were also decreased 8 and 24 h, respectively, after challenge in the peritoneal fluid with cetirizine treatment. MIF stimulates IL-8 production in A431 cells. We found that MIF production in A431 cells was inhibited by 10 microm cetirizine. Consistent with this, cetirizine significantly inhibited MIF-induced IL-8 production. CONCLUSION: These results suggest that cetirizine exerts its anti-inflammatory effects by inhibiting MIF as well as IL-8 production, such as those involved in inflammatory allergic skin disease, suggesting a broad spectrum of action beyond its mere H1-receptor-antagonistic function.

Rapid remission of severe pruritus from angiolymphoid hyperplasia with eosinophilia by pulsed dye laser therapy.

A 48-year-old Japanese woman with angiolymphoid hyperplasia with eosinophilia (ALHE) was successfully treated with a flashlamp pulsed dye laser (585 nm, 450 micros pulse duration). The lesion was severely pruritic and had been enlarging slowly for 2 years but was resistant to conventional therapies, including topical, intralesional, and systemic corticosteroid, and cryotherapy. The severe pruritus immediately improved after the first treatment using the pulsed dye laser. The erythema and papules gradually improved without scarring and this was followed by further five treatments over approximately a 4-month interval. No clinical recurrences have been observed 1 year after completion of the treatment. We think that pulsed dye laser therapy is an effective treatment for ALHE in both Japanese as well as Caucasian patients. Pulsed dye laser therapy is also helpful in reducing the pruritus in ALHE patients.

Erythrinan alkaloids and isoflavonoids from Erythrina poeppigiana.

A new erythrinan alkaloid, 8-oxo-alpha-erythroidine epoxide, was isolated from wood of Erythrina poeppigiana together with the five known compounds, 8-oxo-alpha-erythroidine, erystagallin C, alpinumisoflavone, erythrinin C and eryvarin A. Their structures were elucidated on the basis of spectroscopic evidence.

Low M(r) protein tyrosine phosphatase inhibits growth and migration of vascular smooth muscle cells induced by platelet-derived growth factor.

Vascular smooth muscle cell (VSMC) migration and growth are positively regulated by protein tyrosine phosphorylation. Therefore, a dephosphorylation process controlled by protein tyrosine phosphatases (PTPs) must also be critical. The present study identified six cytoplasmic PTPs expressed in VSMCs: low M(r) protein tyrosine phosphatase (LMW-PTP), SHP-2, PTP36, PTP2, PTP1B, and FAP1. We further examined the functions of LMW-PTP in VSMCs using the adenovirus-mediated gene transfer of recombinant LMW-PTP. PDGF-induced activation of p38, but not of ERK MAP kinase, was blocked by LMW-PTP. LMW-PTP as well as the p38 inhibitor SB203580 inhibited DNA synthesis and cell migration upon PDGF stimulation. LMW-PTP dephosphorylated activated PDGF receptors in NIH3T3 cells, but not in VSMCs. Thus, LMW-PTP negatively regulates PDGF functions by inhibiting the p38 pathway in VSMCs although its substrate is unclear. These findings strongly demonstrate that PTPs are important as negative regulators for VSMC growth and migration, processes that are closely related to the progression of atherosclerosis.

Revised structures for senegalensin and euchrenone b(10).

Two prenylated isoflavones (1 and 2) with a hydroxyisopropyldihydrofuran moiety have been isolated from the wood of Erythrina suberosa var. glabrescence. The structure of compound 1 was in agreement with that of the previously reported senegalensin, isolated from the stem bark of Erythrina senegalensis. The structure of senegalensin was revised from structure 2 to structure 1 by spectroscopic means. Compound 2, the regioisomer of 1, was confirmed as euchrenone b(10) by comparison with the spectral data of the reported euchrenone b(10), isolated from the roots of Euchresta horsfieldii. The structure of 2 was established by 2D NMR spectroscopic analysis and by the X-ray crystallographic analysis of its p-bromobenzoyl derivative (2b).

Effects of plaque control on the patency and occlusion of dentine tubules in situ.

To elucidate the nature of dentine hypersensitivity, the effects of plaque control on the patency and occlusion of dentinal tubules were investigated systematically in situ using human dentine slabs embedded in partial dentures. The dentine slabs were divided into three groups. In group I, the dentine slabs were kept in an oral cavity without plaque control. In group II, plaque was removed mechanically by brushing. Plaque control was carried out chemically using chlorhexidine in group III. After being kept in the oral cavities for 1, 2 and 3 weeks, the slabs were removed from the partial denture, followed by SEM observation to determine the morphological changes of the dentinal tubules. When no attempt was made to remove plaque, the diameter of tubule orifices increased to 390% of the original values within 3 weeks. In contrast, dentinal tubules were found to be occluded, i.e. the tubule orifices became <20% of the original value within 1 week when plaque control efforts were made, using either method of plaque control. We conclude that plaque control plays one of the key roles in the patency versus occlusion of dentinal tubules, and thus in the aetiology and natural reparative process of dentine hypersensitivity.