Liver disease among patients with psoriasis: the Malaysian Psoriasis Registry.

BACKGROUND: Therapeutic options may be limited for patients with psoriasis who have concomitant liver disease (PsL). OBJECTIVES: We aimed to report the frequency of liver disease among patients with psoriasis, and describe the clinical features, treatment modalities and quality of life. METHODS: This was a multicentre cross-sectional study of patients with psoriasis notified to the Malaysian Psoriasis Registry (MPR) from January 2007 to December 2018. RESULTS: Of 21 735 patients with psoriasis, 174 (0.8%) had liver disease. The three most common liver diseases were viral hepatitis (62.1%), fatty liver (14.4%) and liver cirrhosis (10.9%). The male-to-female ratio was 3.8 : 1. Mean age (SD) of onset of psoriasis was higher in those with liver disease vs. those without [37.25 years (13.47) vs. 33.26 years (16.96), P < 0.001]. Patients with PsL, compared with those without liver disease, had a higher rate of dyslipidaemia (27.5% vs. 16.4%, P < 0.001), hypertension (33.9% vs. 23.7%, P = 0.002), diabetes mellitus (22.4% vs. 15.9%, P = 0.021) and HIV infection (5.3% vs. 0.4%, P < 0.001). Those with PsL were also more likely than those without liver disease to have severe disease [body surface area > 10% and/or Dermatology Life Quality Index (DLQI) > 10] (59.3% vs. 49.9%, P = 0.027), psoriatic arthropathy (21.1% vs. 13.0%, P = 0.002) and nail involvement (78.2% vs. 56.1%, P < 0.001). Also significantly higher in the group with PsL were the use of phototherapy (8.4% vs. 2.6%, P < 0.001), acitretin (7.3% vs. 2.8%, P < 0.001) and ciclosporin (3.0% vs. 0.7%, P < 0.001). Mean DLQI was similar in both groups [9.69 (7.20) vs. 9.62 (6.75), P = 0.88]. CONCLUSIONS: The frequency of patients with PsL in the MPR was 0.8%. Patients with PsL were more likely to be male, had a higher rate of comorbidities, severe disease, and nail and joint involvement than those without liver disease.

[The application of 99Tcm-DTPA orbital SPECT/CT in staging evaluation of thyroid associated ophthalmopathy].

Objective: To explore the application value of 99Tcm-diethylenetriaminepentaacetic acid (DTPA) orbital single photon emission computed tomography/computed tomography (SPECT/CT) in staging evaluation of thyroid associated ophthalmopathy (TAO). Methods: A case-control study. A total of 40 patients with binocular TAO were recruited from May 2019 to December 2019 in the Second Hospital of Dalian Medical University. According to the clinical activity score (CAS) standard, 40 TAO patients were divided into the active group (15 cases) and the inactive group (25 cases), and 10 healthy volunteers were recruited as the control group. All subjects underwent 99Tcm-DTPA orbital SPECT/CT examination, and each subject's CAS, reading results and maximum standardized uptake value (SUVmax) were recorded. The Kruskal-Walis H test was used for the CAS comparison among the three groups. The analysis of variance was used for the SUVmax comparison among the three groups. The comparison between CAS and SUVmax before and after treatment was performed by paired samples Wilcoxon signed rank test and paired-sample t test, and Spearman correlation analysis was performed between SUVmax and CAS. The Kappa test was used to check the consistency between the reading result and CAS's judgment of TAO activity. The receiver operating characteristic curve was used to analyze the diagnostic value of the reading results and SUVmax for TAO. Results: The age difference among the three groups was not statistically significant, and the gender difference was not statistically significant (all P>0.05). The difference in CAS among the three groups was statistically significant (H=39.894; P<0.01). Patients with active TAO showed abnormal concentration and enhancement of nuclides in the orbital tissue, and the uptake of radionuclides was significantly increased, while patients with inactive TAO had a slight increase, and healthy volunteers had no significant or only mild uptake. The SUVmax of the active group (2.24±0.47) was highest, and that of the inactive group (1.57±0.43) was higher than the healthy control group (0.67±0.22). After pairwise comparison, there were statistical differences between groups (all P<0.05). According to Spearman correlation analysis, the SUVmax of all TAO patients was linearly, positively correlated with their CAS (r=0.753; P<0.05). In assessing the clinical activity of TAO, the reading results were consistent with CAS (Kappa value=0.737; P<0.05). Taking the reading results as the standard, the area under the receiver operating characteristic curve (AUC) of SUVmax was 0.992, and the threshold of SUVmax to distinguish between active and inactive periods was 1.850, with a sensitivity of 86.70% and a specificity of 76.00%. Taking CAS results as the standard, the AUC of SUVmax was 0.853, and the threshold of SUVmax to distinguish between active and inactive periods was 1.850, with a sensitivity of 100.00% and a specificity of 87.50%. Five patients had inconsistent SUVmax and CAS. The CAS was ≥3, but the orbits did not show any inflammatory lesions in two of them; the CAS was<3, but the orbits showed inflammatory lesions in three of them. Thirteen active TAO patients with 99Tcm-DTPA orbital SPECT/CT showing significant accumulation of nuclides were given hormone shock therapy 12 times. After treatment, the CAS 2.00 (2.00) was lower than the pre-treatment 3.00 (1.50) score, and the difference was statistically significant (Z=-3.100, P<0.01). The SUVmax after treatment (1.60±0.20) was lower than the pre-treatment value (2.17±0.34), and the difference was statistically significant (t=10.197, P<0.01). Conclusion: 99Tcm-DTPA orbital SPECT/CT can relatively accurately determine the state of orbital inflammation in patients with TAO, and can be used as a useful supplement to evaluate the clinical activity of TAO, helping to guide clinical treatment. (Chin J Ophthalmol, 2021, 57: 830-836).

Ethnopharmacological importance and medical applications of Myrothamnus flabellifolius Welw. (Myrothamnaceae)-A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Myrothamnus flabellifolius Welw. (resurrection plant) is a desiccant-tolerant, woody, and shrubby plant. It is popularly used as a local medicinal herbal tea in South Africa, other Southern Africa nations, and Central Africa. M. flabellifolius is used in treating several ailments including epilepsy, mental disorder, cough, pain, stroke, shingles, diabetes, hypertension, wounds, asthma, kidneys and chest ailments. AIM OF THIS REVIEW: This review focuses on the botanical description, distribution, conservation status, ethnobotany, chemistry and pharmacological properties of M. flabellifolius to spur further research that will promote its sustainable harvesting and commercialization. MATERIAL AND METHODS: A literature search on diverse scientific databases, including Google, Google Scholar, Science Direct, PubMed, Scopus, theses, dissertations and ethnobotanical textbooks, were conducted. RESULTS: The conducted search reveals that M. flabellifolius has many traditional uses that can be categorized into infectious diseases, Well-being, respiratory, inflammation, wound and kidney ailments. M. flabellifolius is a natural caffeine-free medicinal herbal tea reported to have antioxidant, anticancer, antiviral, antidiabetic and antimicrobial properties. Toxicological tests on M. flabellifolius were found scarce with gaps in genotoxicological and in vivo studies. Essential oils and isolated compounds were identified from M. flabellifolius with biological activities such as anticancer, antiinflammation, antimicrobial, antiarthritic, antiulcer, antioxidant and antiviral properties. CONCLUSION: It is envisaged that the current review will add value to more scientific research on M. flabellifolius and enhance/promote the increased interest in the sustainable commercialization of M. flabellifolius herbal tea as well as lead to the validation of unverified ethnobotanical claims.

The utilization of phototherapy in the department of dermatology, Hospital Kuala Lumpur: A 5-year audit.

INTRODUCTION: Ultraviolet phototherapies are important treatment modalities for a wide range of dermatological conditions. We aim to describe the utilization of phototherapy in the Department of Dermatology Hospital Kuala Lumpur. METHODS: This is a 5-year retrospective audit on patients who underwent phototherapy between 2011 and 2015. RESULTS: There were 892 patients, M:F=1.08:1, aged from 4- 88 years, with a median age of 38.8 years who underwent phototherapy. Majority (58.9%) had skin phototype IV, followed by type III (37.7%) and type II (0.7%). There were 697(78.1%) who underwent NBUVB, 136 (15.2%) had topical PUVA, 22(2.5%) had oral PUVA, 12(1.4%) had UVA1 and 23(2.6%) had NBUVB with topical or oral PUVA/UVA1 at different time periods. The indications were psoriasis (46.6%), vitiligo (26.7%), atopic eczema (9.8%), pityriasis lichenoides chronica (5.3%), mycosis fungoides (3.9%), lichen planus (2.5%), nodular prurigo (2.2%), scleroderma (1.2%), alopecia areata (0.7%) and others. The median number of session received were 27 (range 1-252) for NBUVB, 30 (range 1-330) for topical PUVA, 30 (range 3-190) for oral PUVA and 24.5 (range 2-161) for UVA1. The acute adverse effects experienced by patients were erythema (18%), pruritus (16.3%), warmth (3.3%), blister formation (3.1%), cutaneous pain (2.4%), and xerosis (0.8%), skin swelling (0.7%) and phototoxicity (0.2%). CONCLUSION: Narrow-band UVB was the most frequently prescribed phototherapy modality in our center. The most common indication for phototherapy in our setting was psoriasis. Acute adverse events occurred in a third of patients, although these side effects were mild.

Review article: nonclinical and clinical pharmacology, pharmacokinetics and pharmacodynamics of etrolizumab, an anti-ß7 integrin therapy for inflammatory bowel disease.

BACKGROUND: Novel treatments with superior benefit-risk profiles are needed to improve the long-term prognosis of patients with inflammatory bowel disease (IBD). Etrolizumab-a monoclonal antibody that specifically targets ß7 integrins-is currently under phase III clinical evaluation in IBD. AIM: This review summarises the available pharmacological and pharmacokinetic/pharmacodynamic data for etrolizumab to provide a comprehensive understanding of its mechanism of action (MOA) and pharmacological effects. METHODS: Published and internal unpublished data from nonclinical and clinical studies with etrolizumab are reviewed. RESULTS: Etrolizumab exerts its effect via a unique dual MOA that inhibits both leucocyte trafficking to the intestinal mucosa and retention within the intestinal epithelial layer. The gut-selectivity of etrolizumab results from its specific targeting of the ß7 subunit of α4ß7 and αEß7 integrins. Etrolizumab does not bind to α4ß1 integrin, which mediates lymphocyte trafficking to tissues including the central nervous system, a characteristic underlying its favourable safety with regard to progressive multifocal leucoencephalopathy. Phase I/II studies in patients with ulcerative colitis (UC) showed linear pharmacokinetics when etrolizumab was administered subcutaneously at 100 mg or higher once every 4 weeks. This dose was sufficient to enable full ß7 receptor occupancy in both blood and intestinal tissues of patients with moderate to severe UC. The phase II study results also suggested that patients with elevated intestinal expression of αE integrin may have an increased likelihood of clinical remission in response to etrolizumab treatment. CONCLUSION: Etrolizumab is a gut-selective, anti-ß7 integrin monoclonal antibody that may have therapeutic potential for the treatment of IBD.

Therapeutic efficacy of atypical antipsychotic drugs by targeting multiple stress-related metabolic pathways.

Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic-pituitary-adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus. To evaluate the effects of AAPDs (such as clozapine, risperidone and aripiprazole) on stress, we compared neurochemical profile variations in the PFC and hippocampus between rat models of chronic unpredictable mild stress (CUMS) for HPA axis activation and of long-term dexamethasone exposure (LTDE) for HPA axis inhibition, using an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS)-based metabolomic approach and a multicriteria assessment. We identified a number of stress-induced biomarkers comprising creatine, choline, inosine, hypoxanthine, uric acid, allantoic acid, lysophosphatidylcholines (LysoPCs), phosphatidylethanolamines (PEs), corticosterone and progesterone. Specifically, pathway enrichment and correlation analyses suggested that stress induces oxidative damage by disturbing the creatine-phosphocreatine circuit and purine pathway, leading to excessive membrane breakdown. Moreover, our data suggested that the AAPDs tested partially restore stress-induced deficits by increasing the levels of creatine, progesterone and PEs. Thus, the present findings provide a theoretical basis for the hypothesis that a combined therapy using adenosine triphosphate fuel, antioxidants and omega-3 fatty acids as supplements may have synergistic effects on the therapeutic outcome following AAPD treatment.

Vitamin D levels in 87 Asian patients with cutaneous lupus erythematosus: a case-control study.

BACKGROUND: Cutaneous lupus erythematosus (CLE) is an autoimmune disease, often exacerbated by sun exposure. Patients are encouraged to avoid sun exposure, therefore predisposing them to vitamin D deficiency. AIM: To investigate the prevalence of and risk factors for vitamin D deficiency in patients with CLE. METHODS: Total serum 25-hydroxy vitamin D (25(OH)D) was measured in 87 consecutive patients with CLE and in 79 controls. Clinical characteristics, disease severity, medications used and lifestyle factors were analysed and compared to determine risk factors for inadequate (25(OH)D), defined as a serum (25(OH)D) level of < 20 µg/L. RESULTS: We found that 51% (n = 44) of the patients with CLE had 25(OH)D levels of < 20 µg/L compared with 73% (n = 58) of the controls (P < 0.01). No significant differences in (25(OH)D) levels were found between cases and controls with regard to age, sex, ethnicity, smoking, sun exposure, sunblock use or vitamin D supplementation. Treatment with antimalarials showed a statistically significant association with lower vitamin D levels. CONCLUSION: Low levels of vitamin D were found in both patients with CLE and controls. Despite being on vitamin D supplementation and living in an equatorial location, our Asian patients with CLE still had low levels of vitamin D. It is therefore important to ensure adequate vitamin D supplementation in patients with CLE, especially for those who are on antimalarial therapy.

Prebiotic-supplemented partially hydrolysed cow's milk formula for the prevention of eczema in high-risk infants: a randomized controlled trial.

BACKGROUND: Prevention guidelines for infants at high risk of allergic disease recommend hydrolysed formula if formula is introduced before 6 months, but evidence is mixed. Adding specific oligosaccharides may improve outcomes. OBJECTIVE: To evaluate whether partially hydrolysed whey formula containing oligosaccharides (0.8 g/100 ml) (pHF-OS) can prevent eczema in high-risk infants [ISRCTN65195597]. METHODS: We conducted a parallel-group, multicentre, randomized double-blind controlled trial of pHF-OS vs standard cow's milk formula. Infants with a family history of allergic disease were randomized (stratified by centre/maternal allergy) to active (n = 432) or control (n = 431) formula until 6 months of age if formula was introduced before 18 weeks. Primary outcome was cumulative incidence of eczema by 12 months in infants randomized at 0-4 weeks (375 pHF-OS, 383 control). Secondary outcomes were cumulative incidence of eczema by 12 or 18 months in all infants randomized, immune markers at 6 months and adverse events. RESULTS: Eczema occurred by 12 months in 84/293 (28.7%) infants allocated to pHF-OS at 0-4 weeks of age, vs 93/324 (28.7%) control (OR 0.98 95% CI 0.68, 1.40; P = 0.90), and 107/347 (30.8%) pHF-OS vs 112/370 (30.3%) control in all infants randomized (OR 0.99 95% CI 0.71, 1.37; P = 0.94). pHF-OS did not change most immune markers including total/specific IgE; however, pHF-OS reduced cow's milk-specific IgG1 (P < 0.0001) and increased regulatory T-cell and plasmacytoid dendritic cell percentages. There was no group difference in adverse events. CONCLUSION: pHF-OS does not prevent eczema in the first year in high-risk infants. The immunological changes found require confirmation in a separate cohort.

Chronic stress causes neuroendocrine-immune disturbances without affecting renal vitamin D metabolism in rats.

INTRODUCTION: Vitamin D (VD) insufficiency has been repeatedly observed in the medical conditions associated with inflammation, such as cardiovascular disease, diabetes and depression. However, contrasting to the observational evidence, randomized trials of VD supplementation failed to demonstrate such link. Given the recent evidence that the inflammatory process can in turn alter VD metabolism, it has been hypothesized that the insufficient VD status could be the result rather than the cause of chronic inflammation involved in the onset of depression and other disease conditions. MATERIALS AND METHODS: Chronic mild stress (CMS) is a valid animal model of depression that accompanied with neuroendocrine-immune disturbances. In the present research, we assessed serum VD concentrations and renal expression of the cytochromes P450 enzymes involved in VD activation (CYP27B1) and catabolism (CYP24A1) of rats following 8-week exposure to CMS. RESULTS: While CMS induced the rats to a depression-like state and increased serum levels of the proinflammatory cytokines and corticosterone, and the antidepressant, sertraline, mitigated depression-like behaviors and neuroendocrine-immune disturbances, neither the stress regimen nor sertraline significantly affected endocrine metabolism of VD. CONCLUSION: Our data suggest that the stress-induced neuroendocrine-immune disturbances may account for the development of depression, but are not responsible for the insufficient VD status that frequently observed in depressed patients.

Heterogeneous interaction of SiO2 with N2O5: aerosol flow tube and single particle optical levitation-Raman spectroscopy studies.

Silica (SiO2) is an important mineral present in atmospheric mineral dust particles, and the heterogeneous reaction of N2O5 on atmospheric aerosol is one of the major pathways to remove nitrogen oxides from the atmosphere. The heterogeneous reaction of N2O5 with SiO2 has only been investigated by two studies previously, and the reported uptake coefficients differ by a factor of >10. In this work two complementary laboratory techniques were used to study the heterogeneous reaction of SiO2 particles with N2O5 at room temperature and at different relative humidities (RHs). The uptake coefficients of N2O5, γ(N2O5), were determined to be (7.2 ± 0.6) × 10(-3) (1σ) at 7% RH and (5.3 ± 0.8) × 10(-3) (1σ) at 40% RH for SiO2 particles, using the aerosol flow tube technique. We show that γ(N2O5) determined in this work can be reconciled with the two previous studies by accounting for the difference in geometric and BET derived aerosol surface areas. To probe the particle phase chemistry, individual micrometer sized SiO2 particles were optically levitated and exposed to a continuous flow of N2O5 at different RHs, and the composition of levitated particles was monitored online using Raman spectroscopy. This study represents the first investigation into the heterogeneous reactions of levitated individual SiO2 particles as a surrogate for mineral dust. Relative humidity was found to play a critical role: while no significant change of particle composition was observed by Raman spectroscopy during exposure to N2O5 at RH of <2%, increasing the RH led to the formation of nitrate species on the particle surface which could be completely removed after decreasing the RH back to <2%. This can be explained by the partitioning of HNO3 between the gas and adsorbed phases. The atmospheric implications of this work are discussed.

The role of seasonal grass pollen on childhood asthma emergency department presentations.

BACKGROUND: Few studies have focused on the role of grass pollen on asthma emergency department (ED) presentations among children. None have examined whether a dose-response effect exists between grass pollen levels and these asthma exacerbations. OBJECTIVES: To examine the association between increasing ambient levels of grass pollen and asthma ED presentations in children. To determine whether these associations are seen only after a thunderstorm, or whether grass pollen levels have a consistent influence on childhood asthma ED visits during the season. METHODS: A short time series ecological study was conducted for asthma presentations to ED among children in Melbourne, Victoria, and grass pollen, meteorological and air quality measurements recorded during the selected 2003 period. A semi-parametric Poisson regression model was used to examine dose-response associations between daily grass pollen levels and mean daily ED attendance for asthma. RESULTS: A smoothed plot suggested a dose-response association. As ambient grass pollen increased to about 19 grains/m(3) , the same day risk of childhood ED presentations also increased linearly (P < 0.001). Grass pollen levels were also associated with an increased risk in asthma ED presentations on the following day (lag 1, P < 0.001). CONCLUSION: This is the first study to establish a clear relationship between increased risk of childhood asthma ED attendance and levels of ambient grass pollen below 20 grains/m(3) , independent of any impact of thunderstorm-associated asthma. These findings have important implications for patient care, such as asthma management programs that notify the general public regarding periods of high grass pollen exposure, as well as defining the timing of initiation of pollen immunotherapy.

The use of konjac glucomannan hydrolysates to recover healthy microbiota in infected vaginas treated with an antifungal agent.

The aim of this study was to evaluate how konjac glucomannan hydrolysates (GMH) could support the healthy re-colonisation of vaginal microflora post infections. A total of 26 female patients (12 controls and 14 treatments) aged 18 to 25 suffering from vaginal infection were recruited for this study. Patients were assigned randomly into two groups to receive a standard antifungal treatment or a standard antifungal treatment plus pessary capsules containing 200 mg GMH (twice a week for thirty days). Patients were assessed on day zero, sixteen and thirty of the trial. Several parameters were determined including yeast and bacterial counts, the KOH test, pH, Gram staining and wet mount microscopic observations. The results showed that the counts of Candida were diminished completely with antifungal treatment for both groups. However, the total bacterial counts increased with time in the GMH pessary group unlike the control. The normalised average KOH scores were reduced sharply with time in both groups although in the control group scores started to increase after sixteen days. The normalised average white blood cell scores also decreased with time for both groups. Epithelial cell scores decreased only for the GMH pessary group while clue cells and yeast-like fungi decreased with time for both control and GMH pessary groups. These results indicate the improvement of vaginal health recovery (post antifungal treatment for Candida infection) and especially the presence of healthy microflora due to the introduction of GMH in the vagina. The data indicate that it would be worth examining further the health benefits of GMH in a vaginal health format with a view to employing the material as a prophylactic or therapeutic agent. It provides an alternative approach to reducing vaginal infections and promoting consumer health.

Lymphomatoid papulosis: is a second lymphoma commoner among East Asians?

BACKGROUND: Lymphomatoid papulosis (LyP) is a low-grade cutaneous lymphoma, which lies within the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Around 10-20% of LyP cases are associated with a second lymphoma. AIM: To analyse a cohort of Asian patients with LyP, diagnosed from 1987 to 2007 at the National Skin Centre (NSC), Singapore, in terms of epidemiology, treatment and association with a second lymphoma. METHODS: Patients were identified through the NSC clinical and histological databases. RESULTS: During this period, 13 patients were diagnosed with LyP based on clinicopathological criteria. The mean age at diagnosis was 41 years, the male : female ratio was 2.3 : 1, and 92% of the patients were Chinese. Recurrent papulonecrotic lesions were present for a mean of 3 years before diagnosis. Treatment of LyP comprised monotherapy (n = 4) or combination therapy (n = 9) using corticosteroids, oral antibiotics, methotrexate and/or phototherapy. Mean duration of follow-up was 6.4 years. Eight patients (61.5%) were diagnosed with a second lymphoma, either before (n = 2), concurrently with (n = 1) or after (n = 5) the diagnosis of LyP. Mycosis fungoides (MF) was the commonest lymphoma (78%, n = 7), followed by primary cutaneous anaplastic large-cell lymphoma (12%, n = 2). There was one death (mortality rate 7.7%), which occurred in a patient who had developed stage IIA MF after LyP, which subsequently progressed to systemic T-cell lymphoma. CONCLUSIONS: LyP is a chronic, relapsing disease with considerable morbidity, but an overall good prognosis. A strikingly large proportion of our Asian patients (61.5%) had a second lymphoma, compared with previous studies. This emphasizes the importance of regular lifetime surveillance for associated lymphomas in all patients with LyP.

First Report of Sooty Blotch and Flyspeck Caused by Species of Dissoconium, Mycosphaerella, and Peltaster on Hawthorn Fruit in China.

Sooty blotch and flyspeck (SBFS), a disease complex comprised of as many as 30 putative species of fungi, occurs on the cuticle of pome fruits in moist production regions worldwide, inciting cosmetic damage that causes significant economic losses (1). Chinese hawthorn (Crataegus pinnatifida Bge.) is an economically important tree species in China. Its fruit are sold fresh or dried and are used as a culinary spice as well as an ingredient in Chinese traditional medicine. In October of 2007, Chinese hawthorn fruit exhibiting SBFS signs were sampled from supermarkets in Yangling, Shaanxi Province and Luoyang, Henan Province, China. Thalli directly from the hawthorn fruit were transferred onto potato dextrose agar (PDA) slants under a dissecting microscope and cultured at 22 ± 1°C in darkness. DNA was extracted from pure isolates and the internal transcribed spacer (ITS) region of the nuclear ribosomal DNA (nrDNA) was amplified and sequenced using primers ITS-1F and ITS4 (3). Phylogenetic analysis of the ITS sequences revealed that the 35 isolates generated in this study included five species in three genera: Dissoconium sp. (18 isolates), Mycosphaerella sp. (5 isolates), and Peltaster sp. 1 (4 isolates), Peltaster sp. 2 (4 isolates), and Peltaster sp. 3 (4 isolates). To fulfill Koch's postulates and verify that these fungi could also infest apple fruit, two representative isolates of each putative species were inoculated onto mature intact hawthorn and apple (cv. Fuji) fruit that had been surface disinfested with 75% ethanol and allowed to dry. Inoculum was prepared by comminuting 1-month-old cultures growing on PDA into a suspension of mycelial fragments and conidia (105 to ~106 CFU/ml) in a blender with sterile deionized water (SDW). Each isolate was inoculated on three hawthorn and three apple fruit by using cotton swabs. As controls, two surface-disinfested hawthorn and apple fruit were swabbed with SDW. After the inoculated hawthorn and apple fruit had been incubated in a moist chamber at 22 ± 1°C for 1 month, all inoculated hawthorn and apple fruit exhibited SBFS signs similar to those of the original colonies on hawthorn fruit, but the controls did not. Reservoir hosts have been inferred to play an important role in SBFS by providing the fungi with overwintering habitat and inoculum for infestations on apple. Many reservoir hosts have been reported in the United States and Japan (2). To our knowledge, this is the first report of fungi in the SBFS complex on hawthorn fruit and the first confirmation that fungi growing on hawthorn fruit can produce SBFS signs on apple fruit. These results identify hawthorn as a potential inoculum source for SBFS in apple orchards. References: (1) J. C. Batzer et al. Mycologia 97:1283, 2005. (2) K. Hemnani et al. Phytopathology 98(suppl):S66, 2008. (3) T. J. White et al. PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, 1990.

Quantitative objective markers for upper and lower motor neuron dysfunction in ALS.

OBJECTIVE: To investigate the value of objective biomarkers for upper (UMN) and lower (LMN) motor neuron involvement in ALS. METHODS: We prospectively studied 64 patients with ALS and its subsets using clinical measures, proton MR spectroscopic imaging ((1)H MRSI), diffusion tensor imaging, transcranial magnetic stimulation, and the motor unit number estimation (MUNE) at baseline and every 3 months for 15 months and compared them with control subjects. RESULTS: (1)H MRSI measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration were markedly reduced in ALS (p = 0.009) and all UMN syndromes combined (ALS, familial ALS [fALS], and primary lateral sclerosis; p = 0.03) vs control values. Central motor conduction time to the tibialis anterior was prolonged in ALS (p < 0.0005) and combined UMN syndromes (p = 0.001). MUNE was lower in ALS (p < 0.0005) and all LMN syndromes combined (ALS, fALS, and progressive muscular atrophy; p = 0.001) vs controls. All objective markers correlated well with the ALS Functional Rating Scale-Revised, finger and foot tapping, and strength testing, suggesting these markers related to disease activity. Regarding changes over time, MUNE changed rapidly, whereas neuroimaging markers changed more slowly and did not significantly differ from baseline. CONCLUSIONS: (1)H MR spectroscopic imaging measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration and ratio of NAA to creatine, central motor conduction time to the tibialis anterior, and motor unit number estimation significantly differed between ALS, its subsets, and control subjects, suggesting they have potential to provide insight into the pathobiology of these disorders.

VITATOPS, the VITAmins TO prevent stroke trial: rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669) (ISRCTN74743444).

BACKGROUND: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke, dementia and depression. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B(12) and vitamin B(6), it is not known whether lowering tHcy, by means of B vitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. AIM: To determine whether the addition of B-vitamin supplements (folic acid 2 mg, B(6) 25 mg, B(12) 500 microg) to best medical and surgical management will reduce the combined incidence of stroke, myocardial infarction (MI) and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. DESIGN: A prospective, international, multicentre, randomised, double blind, placebo-controlled clinical trial. SETTING: One hundred and four medical centres in 20 countries on five continents. SUBJECTS: Eight thousand (6600 recruited as of 5 January, 2006) patients with recent (<7 months) stroke (ischaemic or haemorrhagic) or TIA (brain or eye). RANDOMISATION: Randomisation and data collection are performed by means of a central telephone service or secure internet site. INTERVENTION: One tablet daily of either placebo or B vitamins (folic acid 2 mg, B(6) 25 mg, B(12) 500 mug). PRIMARY OUTCOME: The composite of stroke, MI or death from any vascular cause, whichever occurs first. Outcome and serious adverse events are adjudicated blinded to treatment allocation. SECONDARY OUTCOMES: TIA, unstable angina, revascularisation procedures, dementia, depression. STATISTICAL POWER: With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8% among patients assigned placebo, the study will have at least 80% power to detect a relative reduction of 15% in the incidence of the primary outcome among patients assigned B vitamins (to 6.8%/year), applying a two-tailed level of significance of 5%. CONCLUSION: VITATOPS aims to recruit and follow-up 8000 patients between 1998 and 2008, and provide a reliable estimate of the safety and effectiveness of folic acid, vitamin B(12), and vitamin B(6) supplementation in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke throughout the world.

Sustained homocysteine-lowering effect over time of folic acid-based multivitamin therapy in stroke patients despite increasing folate status in the population.

BACKGROUND AND AIMS: It is uncertain what impact increasing voluntary folate fortification may be having on the statistical power of randomized trials testing the homocysteine hypothesis of atherothrombosis. The objective of this study was to determine whether there has been a change in folate status between 1998 and 2002 in stroke patients randomized into the VITAmins TO Prevent Stroke (VITATOPS) Study at a single center in Perth, Australia, and what impact this may have had on the magnitude of the homocysteine-lowering effect achieved over time with folic acid-based multivitamin therapy. METHODS: We conducted a randomized, double-blind, placebo-controlled study involving 285 patients with stroke or transient ischemic attack who were recruited between 1998 and 2002 and randomized to long-term folic acid 2.0 mg/day, pyridoxine 25 mg/day and cobalamin 0.5 mg/day (active VITATOPS medication) or placebo. Fasting plasma total homocysteine, red cell folate, serum cobalamin and serum pyridoxine levels were measured at baseline and 6 months, and the change in blood levels over 4 time quartiles and differences in levels between the two randomized treatments were examined. RESULTS: Between 1998 and 2002, there was a significant rise in baseline mean red cell folate levels over 4 time quartiles among the entire stroke cohort (723.3, 780.1, 922.6 and 1,023.7 nmol/l in the first, second, third and fourth quartiles, respectively; p < 0.0001), but this was not associated with a spontaneous reduction in mean baseline total homocysteine levels during the same time period (12.7, 14.3, 12.1 and 12.8 micromol/l in the first, second, third and fourth quartiles, respectively; p = 0.55). The homocysteine-lowering effect of the active VITATOPS trial medication at 6 months after randomization also did not change significantly between 1998 and 2002 (difference between randomized groups: -4.1, -4.1, -3.1 and -3.6 micromol/l in the first, second, third and fourth quartiles, respectively; p = 0.56). CONCLUSIONS: The homocysteine-lowering effect of the active VITATOPS trial medication has not attenuated significantly in the past 5 years despite increasing voluntary fortification of foods with folic acid as reflected by a progressive rise in baseline folate status. These data suggest that in the continuing absence of a program of mandatory folate fortification of food in populations served by centers participating in the VITATOPS trial, the study will remain adequately powered to test the homocysteine-lowering hypothesis for which it was designed.