Daily patterns in parasite processes: diel variation in fish louse transcriptomes.

Parasites, similar to all other organisms, time themselves to environmental cues using a molecular clock to generate and maintain rhythms. Chronotherapeutic (timed treatment) techniques based on such rhythms offer great potential for improving control of chronic, problematic parasites. Fish lice are a key disease threat in aquaculture, with current control insufficient. Assessing the rhythmicity of fish lice transcriptomes offers not only insight into the viability of chronotherapy, but the opportunity to identify new drug targets. Here, for the first known time in any crustacean parasite, diel changes in gene transcription are examined, revealing that approximately half of the Argulus foliaceus annotated transcriptome displays significant daily rhythmicity. We identified rhythmically transcribed putative clock genes including core clock/cycle and period/timeless pairs, alongside rhythms in feeding-associated genes and processes involving immune response, as well as fish louse drug targets. A substantial number of gene pathways showed peak transcription in hours immediately preceding onset of light, potentially in anticipation of peak host anti-parasite responses or in preparation for increased feeding activity. Genes related to immune haemocyte activity and chitin development were more highly transcribed 4 h post light onset, although inflammatory gene transcription was highest during dark periods. Our study provides an important resource for application of chronotherapy in fish lice; timed application could increase efficacy and/or reduce dose requirement, improving the current landscape of drug resistance and fish health while reducing the economic cost of infection.

Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

Concentrations of mercury in tissues of beluga whales (Delphinapterus leucas) from several communities in the Canadian Arctic from 1981 to 2002.

Beluga whales have been hunted for food by Native People in the Canadian Arctic since prehistoric time. Here we report the results of analyses of total mercury in samples of liver, kidney, muscle and muktuk from collections over the period 1981-2002. We compare these results with human consumption guidelines and examine temporal and geographic variation. Liver has been analyzed more frequently than other organs and it has been used as the indicator organ. Mercury accumulates in the liver of the whales over time so that the whale ages are usually linked statistically to their levels of mercury in liver. Virtually all the samples of 566 animals analyzed contained mercury in liver at concentrations higher than the Canadian consumption guideline of 0.5 microg g-1 (wet weight) for fish. (There is no regulatory guideline for concentrations in marine mammals in Canada.) Samples from locations in the Mackenzie Delta in the western Canadian Arctic and from Pangnirtung in the eastern Canadian Arctic were obtained more often than from other location and these offered the best chances to determine whether levels have changed over time. Statistical outlier points were removed and the regressions of (ln) mercury in liver on age were used to calculate the level of mercury in whales of age 13.1 years in order to compare age-adjusted levels at different locations. These age-adjusted levels and also the slopes of regressions suggested that levels have increased in the Mackenzie Delta over the sampling period although not in a simple linear fashion. Other locations had fewer collections, generally spread over fewer years. Some of them indicated differences between sampling times but we could not establish whether these differences were simply temporal variation or whether they were segments of a consistent trend. For example, the levels in whales from Arviat were considerably higher in 1999 than in 1984 but we have only two samples. Similarly, samples from Iqaluit in 1994 exceeded considerably those in 1993 and the interval seems too short to reflect any regional temporal trend and more likely represent an extreme case of year-to-year variation. Previous analyses of data from geographically distinct groups had suggested that whales in the western Canadian Arctic had higher levels of mercury than those from the eastern Canadian Arctic. The present analysis suggests that such regional differences have diminished and are no longer statistically significant. No site has indicated significant decreases in more recent samples. The levels of total mercury in the most analyzed organs fell in the order of liver (highest levels), kidney, muscle and muktuk (lowest level). While muktuk had the lowest level of the organs most frequently analyzed, it is the preferred food item from these whales and it still exceeded the consumption guideline in most instances.

Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib.

BACKGROUND: Cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs are intended to preserve cyclo-oxygenase-1-mediated gastroprotection and platelet function, whilst inhibiting cyclo-oxygenase-2-mediated inflammation. AIM: To assess the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib vs. non-selective non-steroidal anti-inflammatory drugs. METHODS: Two randomized, double-blind, placebo- and active-controlled studies were performed: (i) daily faecal red blood cell loss was measured in 62 subjects receiving etoricoxib (120 mg once daily), ibuprofen (800 mg t.d.s.) or placebo for 28 days; (ii) the incidence of endoscopically detectable gastric/duodenal ulcers was determined in 742 osteoarthritis or rheumatoid arthritis patients receiving etoricoxib (120 mg once daily), naproxen (500 mg b.d.) or placebo over 12 weeks. RESULTS: In the first study, the between-treatment ratio of faecal blood loss for etoricoxib vs. placebo (1.06) was not significantly different from unity; however, the ratios for ibuprofen vs. placebo (3.26) and etoricoxib (3.08) were significantly greater than unity (P < 0.001). In the second study, the incidence of ulcers of > or = 3 mm with naproxen (25.3%) was significantly higher than that with etoricoxib (7.4%) or placebo (1.4%; P < 0.001); the results were similar for ulcers of > or = 5 mm. CONCLUSIONS: The reduced toxicity of etoricoxib (less faecal blood loss and fewer endoscopically detectable lesions) suggests that use of this drug will may be associated with a reduced incidence of gastrointestinal perforations, ulcers and bleeds.

Bismuth-based quadruple therapy with bismuth subcitrate, metronidazole, tetracycline and omeprazole in the eradication of Helicobacter pylori.

BACKGROUND: A previous study showed that 14 days of qid bismuth-based triple therapy with tetracycline 500 mg, metronidazole 250 mg and colloidal bismuth subcitrate 120 mg resulted in excellent Helicobacter pylori eradication rates (89.5%). The present study looked at a shorter treatment period by adding omeprazole and by reducing the dose of tetracycline. METHODS: One hundred sixty-one patients with H pylori confirmed by histology and (13)carbon urea breath test were included in the study. They were treated for seven days with bismuth subcitrate 120 mg plus metronidazole 250 mg plus tetracycline 250 mg qid plus omeprazole 20 mg bid (OBMT). Patients were 18 to 75 years of age and had dyspepsia with or without a history of peptic ulcer. Patients with irritable bowel syndrome, active ulcer or previous attempt at eradication, or those who had used antibiotics or antiulcer drugs in the previous 30 days were excluded. Eradication was determined by two (13)carbon urea breath tests done one and three months, respectively, after treatment. Strains with minimal inhibitory concentrations of 8 microg/mL or higher were considered to be resistant to metronidazole. RESULTS: The overall per protocol eradication rate was 84%-89.5% in metronidazole-sensitive and 70.8% in metronidazole-resistant strains. Modified intent-to-treat analysis resulted in a 80% eradication rate--82.5% in metronidazole-sensitive and 66.7% in metronidazole-resistant strains. Only one patient discontinued treatment because of adverse events. CONCLUSIONS: The OBMT regimen used in this study is safe and effective against metronidazole-sensitive H pylori strains.

Efficacy of three insect repellents against the malaria vector Anopheles arabiensis.

Three commercial repellents marketed in South Africa: Bio-Skincare (BSC, oils of coconut, jojoba, rapeseed and vitamin E), Mosiguard towelletes with 0.574 g quwenling (p-menthane-3,8-diol, PMD) and the standard deet (15% diethyl-3-methylbenzamide, Tabard lotion), were compared against a laboratory colony of the mosquito Anopheles arabiensis Patton (Diptera: Culicidae), the predominant malaria vector in South Africa. Human forearms were treated with 1.2 g BSC, 0.8 g PMD towelette or 0.5 g deet and exposed to 200 hungry An. arabiensis females for 1 min, at intervals of 1-6 h post-treatment. Tests were conducted by three adult male volunteers (aged 30-45 years, crossover controlled test design for 3 consecutive days), using their left arm for treatment and right arm for untreated control. Biting rates averaged 39-52 bites/min on untreated arms. All three repellents provided complete protection against An. arabiensis for up to 3-4 h post-application; deet and PMD gave 90-100% protection up to 5-6h, but BSC declined to only 52% protection 6h post-treatment. These results are interpreted to show that all three repellent products give satisfactory levels of personal protection against An. arabiensis for 4-5 h, justifying further evaluation in the field.

Local plants as repellents against Anopheles arabiensis, in Mpumalanga Province, South Africa.

OBJECTIVE: To assess the repellency effect of three local plants; fever tea (Lippia javanica), rose geranium (Pelargonium reniforme) and lemon grass (Cymbopogon excavatus) against laboratory reared Anopheles arabiensis mosquitoes. DESIGN: A laboratory experimental study. SETTING: Mpumalanga Province, South Africa. SUBJECTS: Three adult male volunteers. MAIN OUTCOME MEASURES: Affordable alternatives to synthetic repellents against biting of Anopheles arabiensis mosquitoes. RESULTS: All three alcohol plant extracts provided significantly more protection (p = 0.012) than alcohol control. The alcohol plant extract of L. javanica provided 76.7% protection against An. arabiensis after a four hour period, and C. excavatus and P. reniforme provided 66.7% and 63.3% protection for three hours, respectively. At five hours post application only L. javanica alcohol extract provided appreciable protection (59.3%) against An. arabiensis. CONCLUSION: The results of this study indicate that L. javanica, P. reniforme and C. excavatus protect against An. arabiensis mosquito bites with the repellent effect of L. javanica lasting significantly longer than that of the other two plants.

Adding once-daily omeprazole 20 mg to metronidazole/amoxicillin treatment for Helicobacter pylori gastritis: a randomized, double-blind trial showing the importance of metronidazole resistance.

OBJECTIVE: We compared the Helicobacter pylori eradication rate after a 14-day treatment with amoxicillin 500 mg t.i.d. and metronidazole 500 mg t.i.d. with or without omeprazole 20 mg once daily. METHODS: This was a randomized, controlled trial in which omeprazole was given in double-blind fashion. Patients with H. pylori-associated gastritis were enrolled in four centers in Canada from July 1991 to January 1994. Eradication of H. pylori was assessed by histological evaluation and culture of endoscopic biopsies obtained from the antrum and corpus of the stomach. RESULTS: The H. pylori eradication rate was 73% (33 of 45) in the omeprazole-amoxicillin-metronidazole group, compared with 66% (31 of 47) in the amoxicillin-metronidazole group. This 7% difference was not statistically significant (p = 0.43, 95% confidence interval for difference -11% to 26%). Metronidazole primary resistance in the prestudy cultures was found more frequently in the omeprazole-amoxicillin-metronidazole group than in the amoxicillin-metronidazole group. Resistance to metronidazole was an important predictor of treatment failure. The H. pylori eradication rate was 61% (19 of 31) for patients infected with metronidazole-resistant H. pylori strains, compared with 91% (30 of 33) eradication for those infected with metronidazole-sensitive strains (p < 0.01). Vaginal candidiasis was reported in four patients. CONCLUSIONS: The H. pylori eradication rate was higher (73%) for omeprazole-amoxicillin-metronidazole than for the dual antibiotic therapy given without omeprazole (66%); however, this difference was not statistically significant. Metronidazole resistance significantly reduces H. pylori eradication rates.

Role of heme-hemopexin in human T-lymphocyte proliferation.

Heme-hemopexin supports and stimulates proliferation of human acute T-lymphoblastic (MOLT-3) cells, suggesting the participation of heme in cell growth and division. MOLT-3 cells express approximately 58,000 hemopexin receptors per cell (apparent Kd 20 nM), of which about 20% are on the cell surface. Binding is dose- and temperature-dependent, and growth in serum-free IMDM medium is stimulated by 100-1000 nM heme-hemopexin, consistent with the high affinity of the receptor for hemopexin, and maximal growth is seen in response to 500 nM complex. Growth was similar in defined minimal medium supplemented with either low concentrations of heme-hemopexin or iron-transferrin, and either of these complexes were about 80% as effective as a serum supplement. Heme-hemopexin, but not apo-hemopexin, reversed the growth inhibition caused by desferrioxamine showing that heme-iron derived from heme catabolism is used for cell growth. Cobalt-protoporphyrin (CoPP)-hemopexin, which binds to the receptor but is not transported intracellularly [Smith et al., (1993) J. Biol. Chem. 268, 7365], also stimulated cell proliferation in serum-free IMDM but did not "rescue" the cells from desferrioxamine. Furthermore, CoPP-hemopexin effectively competed for the hemopexin receptor with heme-hemopexin and diminished its growth stimulatory effects. In addition, protein kinase C (PKC) is translocated to the plasma membrane within 5 min after heme-hemopexin is added to the medium, reaches maximum activity within 5-10 min, and declines to unstimulated levels by 30 min. Heme-hemopexin and CoPP-hemopexin both augmented MOLT-3 cell growth stimulated by serum. Thus, heme-hemopexin not only functions as an iron source for T-cells but occupancy of the hemopexin receptor itself triggers signaling pathway(s) involved in the regulation of cell growth. The stimulation of growth of human T-lymphocytes by heme-hemopexin is likely to be a physiologically relevant mechanism at sites of injury, infection, and inflammation.

Mucosal damage during intestinal anaphylaxis in the rat. Effect of betamethasone and disodium cromoglycate.

In this study, two antiallergic compounds, betamethasone and disodium cromoglycate were tested in an animal model of intestinal anaphylaxis. Rats, immunized with Nippostrongylus brasiliensis, were challenged intravenously with whole worm antigen or saline. Antigen challenge resulted in significant abnormalities: epithelial damage with shorter villi, decreased activity of digestive enzymes, decreased levels of mucosal histamine, a mast cell mediator, and increased blood uptake of [51Cr]EDTA from the lumen. Low-dose betamethasone, 24 and 48 hr before antigen, was not effective in preventing the effects: villus damage and increased [51Cr]EDTA uptake were seen, although mucosal mast cell numbers were significantly reduced by the drug. High-dose betamethasone completely prevented intestinal anaphylaxis: villus height, digestive function, and [51Cr]EDTA recovery in antigen-challenged animals were not significantly different from controls. Mucosal histamine levels and mast cells were significantly reduced in the high dose betamethasone group. Oral disodium cromoglycate did not prevent the abnormalities but provided a slight beneficial effect.

Effect of acupuncture on gastric acid secretion in healthy male volunteers.

Six randomized, placebo controlled studies were performed to investigate the effect of electroacupuncture on gastric acid output in 38 healthy males. Electroacupuncture decreased basal acid output when compared to placebo acupuncture [from 3.50 +/- 0.59 mmol/hr to 2.54 +/- 0.56 mmol/hr (P < 0.05)] as well as sham feeding-stimulated acid output [from 18.52 +/- 2.25 mmol/hr to 5.38 +/- 2.11 mmol/hr (P < 0.005)], but had no effect on the pentagastrin stimulated acid output. The inhibitory effect of acupuncture on sham feeding-stimulated acid output was not affected by local anesthesia of the acupoint, but was prevented by a prior intravenous naloxone injection. Acupuncture did not alter plasma gastrin levels (20.7 +/- 7.6 micrograms/liter, vs control 21.2 +/- 7.2 micrograms/liter) but naloxone increased it (26.1 +/- 14.5 micrograms/liter) (P < 0.05). We conclude that the antisecretory effects of electroacupuncture do not result from decreased gastrin release or decreased parietal cell sensitivity to gastrin, but are mediated through naloxone-sensitive opioid neural pathways and vagal efferent pathways.

The effect of acupuncture on gastrointestinal function and disorders.

Acupuncture has been used empirically in clinical practice in China for several millenia and has recently drawn interest as a mode of anesthesia. Despite extensive investigation, the exact mechanisms of its analgesic action are unknown, but are thought to involve endogenous opioid peptides. Only recently have studies attempted to evaluate the effect of acupuncture on gastrointestinal function and disease. A review of studies from both the Chinese and Western literature supports the efficacy of acupuncture in the regulation of gastrointestinal motor activity and secretion through opioid and other neural pathways. However, no firm conclusion can be drawn about the effectiveness of acupuncture in the treatment of specific gastrointestinal disorders because of the lack of properly randomized controlled trials.

Effects of chronic left vagal stimulation on visceral vagal function in man.

We examined the effects of chronic left vagal electrostimulation on afferent and efferent gastrointestinal vagal function in eight patients. Afferent function was assessed using cortical evoked responses to electrical stimulation of the esophagus and to direct vagal stimulation using the implanted left vagal electrode. Efferent gastrointestinal vagal function was measured by examining the basal, maximal, and sham fed stimulated gastric acid output prior to and with chronic left vagal electrostimulation. Esophageal electrostimulation produced a cortical evoked response consisting of three negative and three positive peaks within 400 msec after stimulation. Prior to vagal electrostimulation the mean conduction velocity of the afferent signal was measured at 8.72 +/- 3.39 m/sec, compatible with A-delta fibers involvement. Basal, maximal, and sham fed acid output were 1.11, 21.87, and 9.37 mmol/hour, respectively. The evoked response to esophageal electrical stimulation was not changed with chronic left vagal electrostimulation. Direct vagal stimulation also produced evoked potentials that were comparable to those obtained with esophageal stimulation. The mean conduction velocity was 6.26 +/- 2.72 m/sec (NS) so that there was no evidence of loss of myelinated fibers with chronic stimulation. No differences were detected in basal (1.29 mmol/h), maximal (21.64 mmol/h), or sham fed stimulated (8.03 mmol/h) acid output, showing that vagal electrostimulation has no effect on either total or vagally mediated acid output, an efferent vagal function. In conclusion, chronic left vagal electrostimulation has no significant adverse effect on gastrointestinal vagal function.

The community care of terminally ill patients.

The authors outline the results of a survey, through interviews or posted questionnaires, of 122 Adelaide general practitioners. General practitioners shared or handed over most aspects of terminal care, particularly the spiritual and social aspects. Comprehensive care for these patients is directly related to the general experience of the general practitioners. The need for improved undergraduate and postgraduate education in terminal illness is stressed.

Effect of selenium deficiency on tissue taurine concentration and urinary taurine excretion in the rat.

The purpose of this study was to determine the effect of selenium deficiency on tissue taurine levels and urinary taurine excretion. Weanling male Sprague-Dawley rats were fed selenium-deficient or selenium-adequate diets for 20 weeks. As selenium deficiency developed, urinary taurine excretion increased in selenium-deficient rats compared to controls. At 12 weeks, the selenium-deficient rats excreted 1.7-fold more taurine than control rats. At the same time plasma glutathione peroxidase was 1.2% of control and plasma glutathione was 226% of control. At 20 weeks, renal taurine was decreased but renal glutathione was increased in selenium-deficient rats compared to controls. Feeding the experimental diet for 6 weeks without methionine supplementation caused a fall in urinary taurine excretion. However, there was no difference between selenium-deficient and control rats. These results indicate that selenium deficiency affects renal handling of taurine in the rat when dietary sulfur amino acids are not restricted.

A reexamination of the role of imagery in learning and memory.

Five experiments were conducted to examine whether the superior recall of concrete over abstract words might be better accounted for in terms of relative differences in the processing of relational and distinctive information rather than redundant verbal and imaginal memory codes. Concrete and abstract word pairs were presented in the standard paired-associated learning task or under conditions intended to affect the nature and extent of relational processing between pair members. Concreteness effects were attenuated or eliminated when relational processing was prevented at encoding (Experiments 3, 4, and 5) or when the use of encoded relations within pairs was prevented at recall (Experiments 1, 2, and 3). The results indicated the viability of an account of concreteness effects in paired-associate learning based on the joint functions of distinctive and relational information. They also remove theoretical constraints imposed on imagery theories by the incorrect assumption of a uniform presence of concreteness effects in memory for word lists.

Prospective comparison of double contrast barium enema plus flexible sigmoidoscopy v colonoscopy in rectal bleeding: barium enema v colonoscopy in rectal bleeding.

Rectal bleeding often heralds serious colonic disease. The literature suggests that colonoscopy is superior to barium enema plus sigmoidoscopy, although no good comparative studies exist. Seventy one patients with overt rectal bleeding had prospectively flexible sigmoidoscopy, double contrast barium enema and colonoscopy completed independently. Against the gold standard, the sensitivity and specificity of colonoscopy were 0.69 and 0.78 respectively for a spectrum of colonic lesions, while for combined flexible sigmoidoscopy and double contrast barium enema these values were 0.80 and 0.56, respectively. When assessing adenoma or carcinoma, colonoscopy was more sensitive at 0.82 v 0.73, while flexible sigmoidoscopy plus double contrast barium enema was superior for detecting diverticular disease. The positive predictive value for colonoscopy was 0.87 against 0.81 for flexible sigmoidoscopy and double contrast barium enema. This study confirms that colonoscopy should be a first line investigation in subjects likely to require biopsy or therapeutic intervention.