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INTRODUCTION — Complementary and alternative medicine (CAM) therapies for allergic rhinitis and conjunctivitis include Chinese herbal medicine (CHM), Ayurvedic medicine, other single and multiple herb preparations, acupuncture, homeopathy, and several other modalities. CAM therapies continue to gain popularity in the United States and throughout the world for the treatment of asthma and allergies.
This review is limited to those therapies about which there is published literature specifically concerning the treatment of allergic rhinitis/conjunctivitis. These therapies include traditional Chinese medicine (TCM), acupuncture, Ayurvedic medicine, a variety of herbal therapies, and several others.
CAM therapies for allergic rhinitis/conjunctivitis are discussed in this topic review. CHM for allergic diseases and CAM therapies for asthma are reviewed elsewhere. (See "Chinese herbal medicine for the treatment of allergic diseases" and "Investigational agents for asthma".)
OVERVIEW — Complementary and alternative medicine (CAM) is commonly defined as a group of diverse medical and healthcare systems, practices, and products that are not generally considered part of the conventional allopathic medical practices. Complementary therapies are used together with conventional allopathic medicine, while alternative therapies are used in place of conventional medicine. More general reviews of the principles of various CAM therapies are also found separately. (See "Overview of herbal medicine and dietary supplements" and "Complementary and alternative medicine in pediatrics" and "Acupuncture" and "Homeopathy".)
Popularity — More than 20 percent of the United States population appears to suffer from an atopic disorder, such as asthma, allergic rhinitis, and atopic dermatitis, and over 42 percent of people (both adults and children) have used CAM for their atopic disorder [1,2]. The popularity of CAM therapies for allergic disease is even greater in some European countries [3]. Thus, it is important to ask patients about the use of CAM therapies in a nonjudgmental manner [4].
The use of CAM is growing in Western countries because of the reputed effectiveness, low cost, and favorable safety profiles of some therapies. Patients are often interested in alternative therapy either because conventional therapies are unsatisfactory or because of concerns about side effects of synthetic drugs [5-7]. The chronic nature of allergic diseases and the paucity of preventive or curative treatments also stimulate interest in CAM therapies [8]. There are marked cultural differences in use of CAM (eg, patients from Southeast Asia commonly use herbal remedies for allergic rhinitis) [9].
Barriers to integration with allopathic medicine — One of the major concerns with CAM is that it is perceived to be "natural" and therefore safe by patients, but an analysis of safety reporting in randomized trials of CAM found that reporting of adverse effects was largely inadequate [10]. Improvement in safety reporting would facilitate integration into routine patient care. However, until this materializes, healthcare providers can familiarize themselves as much as possible with the available scientific literature on CAM. Evidence-based information of CAM therapies is available through several internet sites. (See "Overview of herbal medicine and dietary supplements", section on 'Internet evidence-based resources'.)
Given the high prevalence of allergic diseases and associated costs of the CAM treatments, high quality data about these therapies are needed so that practice guidelines can be established. In the United States, the NCCIH/National Center for Complementary and Integrative Health has been tasked with evaluating mechanisms, efficacy, and safety of botanical medicines through basic science studies, clinical research, and the establishment of dedicated botanical research centers [11].
The design of randomized placebo-controlled studies in CAM is complicated by difficulties in blinding, creating an appropriate placebo (particularly for acupuncture), and designing a control treatment when the mechanisms of actions of the modality in question are poorly delineated (such as homeopathy). Additionally, the difference in philosophy of CAM interventions from conventional health care allows for significant variation in the way CAM modalities are practiced (ie, therapies are often individualized for a particular patient and his/her specific disease state). Finally, the efficacy of CAM therapies may be heavily influenced by the patient's perception of his/her interaction with the provider, which is often more personal than the interaction between patients and allopathic healthcare providers. Thus, results may vary significantly among CAM providers and studies of CAM must also account for the influence of the patient-provider relationship.
TRADITIONAL CHINESE MEDICINE — Traditional Chinese medicine (TCM) includes herbal therapy, acupuncture, massage, and dietary therapy. These practices originated in China and have been used in East Asia for centuries as a part of mainstream medical care. TCM treatments for allergic rhinitis and conjunctivitis are reviewed separately. (See "Chinese herbal medicine for the treatment of allergic diseases", section on 'Therapy for allergic rhinitis and conjunctivitis'.)
ACUPUNCTURE AND ACUPRESSURE — Acupuncture is a component of traditional Chinese medicine (TCM) that was originally thought to work on the principle of redistribution of Qi, the life energy. In TCM, disease is believed to originate from an imbalance of Qi or poor flow of Qi. The difficulties in designing trials of acupuncture are reviewed elsewhere. (See "Acupuncture", section on 'Basic theory' and "Acupuncture", section on 'Difficulties in research'.)
Studies of acupuncture for the treatment of allergic rhinitis have shown mixed results, with the most rigorous studies showing very modest clinical benefit [12-17]. A 2015 practice guideline suggested the potential use of acupuncture, but included limited data supporting its use in allergic rhinitis or allergic conjunctivitis [18].
●A systematic review identified 116 potentially relevant articles, of which 12 met criteria for inclusion by studying needle acupuncture, examining clinically relevant outcomes, and including a control, sham, or comparator treatment group [12]. The results were different for seasonal and perennial allergic rhinitis. There were no effects on seasonal symptoms, although some benefit was apparent for perennial symptoms. The magnitude of effect could not be estimated, although drug therapy could not be reduced as a result of acupuncture in either type of rhinitis.
●A subsequent randomized controlled trial demonstrated statistically significant but clinically modest improvement in the primary endpoint of total nasal symptom score after the fourth week of treatment. Improvement was not sustained one week after completion of the four-week course, but was surprisingly present three weeks later [13].
●In a multicenter randomized trial of 422 patients with seasonal allergic rhinitis to birch and grass pollen (ACUSAR – ACUpuncture in Seasonal Allergic Rhinitis), subjects were treated with eight weeks of acupuncture with rescue antihistamine (RA), sham acupuncture with RA, or RA alone [14]. Rhinitis-related quality of life and antihistamine use were measured after the eight weeks of treatment, an additional eight weeks later, and one year later. When compared with sham acupuncture with RA and RA alone, acupuncture with RA resulted in an improvement of 0.5 points and a reduction in medication use of 0.7 points, where 1 point was equivalent to taking one less 10 mg cetirizine tablet daily. Thus, the benefit was statistically significant, but of questionable clinical importance. In a cost-effectiveness analysis of these data, the authors concluded that while acupuncture did cause small improvements in quality of life, it was very expensive and may not be a cost-effective intervention for allergic rhinitis [19].
Critique of the protocol used in ACUSAR included the use of more needles in the acupuncture patients versus the sham patients (16 compared with 10) and a larger fraction of patients in the acupuncture arm having high expectations for acupuncture efficacy at baseline (85 versus 73 percent) [20]. In addition, the study was performed in two centers in South Korea and China, and pollen counts during the years of treatment and observation, which can dramatically influence results, were not reported. (See "Acupuncture", section on 'Trials for conditions other than pain'.)
In summary, the best trials of acupuncture for allergic rhinitis support limited benefit. Despite this, acupuncture may be a reasonable option for interested patients with relatively mild disease who wish to minimize medication use and find the cost of therapy acceptable.
Acupressure is similar to acupuncture but does not involve needles. Stainless steel pellets in adhesive discs are applied to specified points (acupoints) on the ear, and the pellets are pressed firmly into the skin. In a randomized sham-controlled trial, ear acupressure was studied for the treatment of mild to moderate perennial allergic rhinitis of 245 adults for eight weeks with a follow-up period of 12 weeks [21]. Subjects were treated for 5 to 10 minutes weekly by a practitioner in a clinic and instructed to perform the therapy three times daily at home, for 10 seconds per session. There was a small but statistically significant improvement in sneezing and quality of life in the acupressure group after eight weeks, with additional improvements in most measures of nasal symptoms at the end of the follow-up period compared with the sham group. These findings are interesting, although additional studies will be required to make more definitive recommendations about the utility of this therapy.
AYURVEDA — Ayurvedic medicine is a medical tradition originating from India and derived from the teachings of ancient Hindu healers, which first appeared in text between 1500 and 1000 BC. Like TCM, Ayurvedic therapeutic interventions include yoga, meditation, breathing exercises, and herbal preparations. In its truest form, Ayurveda exists for the "promotion of health" rather than the treatment of specific disease states that have already begun to affect the body.
Ayurvedic herbal therapies have been evaluated in the treatment of allergic rhinitis. Aller-7 is a mixture of seven Indian herbs (Albizia lebbeck, Terminalia chebula, Terminalia bellerica, Phyllanthus emblica, Piper nigrum, Piper longum, and Zingiber officinale) [22]. In vitro studies examining the mixture demonstrated antihistaminic and antiinflammatory properties. In an experimental model using the nonspecific mast cell degranulating agent 48/80 ("antihistamine model"), Aller-7 appeared to be equivalent to cetirizine. In the best human study to date, Aller-7 was compared with placebo in 545 adult patients with allergic rhinitis (171 of whom took part in randomized protocols, while the others were treated in an open label fashion, treated for 12 weeks with 660 mg Aller-7 twice daily by mouth) [23]. Clinically significant effects were noted at 6 and 12 weeks, which included 10 to 20 percent improvement in congestion, rhinorrhea, and sneezing compared with the placebo group in those patients in randomized protocols. Adverse effects were almost twice that of placebo and were largely mild gastrointestinal issues (eg, gastritis, discomfort, and dryness of mouth). Aller-7 is commercially available.
HERBAL THERAPIES (SYSTEMIC) — A variety of herbal preparations may be used by patients with allergic rhinitis and conjunctivitis, although scientific evaluation of herbal products has been limited and only those that have been evaluated in published clinical trials are reviewed here. A 2007 systematic review identified 16 randomized controlled trials that met eligibility criteria [24]. The agents discussed in this section are listed by their English names and their Latin or pharmacopeial names.
Most herbal preparations contain several components, each with potentially varying physiologic and pharmacologic properties. However, herbal therapies that differ by name may contain identical components and thus share similar clinical effects and adverse effects. This is important when trying to analyze studies that attribute a clinical or physiologic property to a specific herbal preparation.
In many countries, herbal medicines are minimally regulated and uncommonly monitored for adverse events by national surveillance systems. However, the increasing popularity of herbal medicines has led to concerns over their safety, quality, and efficacy on the part of health authorities and the general public. In response to these concerns, the World Health Organization has published formal monographs on selected medicinal plants to establish quality standards of herbal products and outline the parameters for their safe and effective use [25]. Safety issues surrounding the use of herbal medications are reviewed elsewhere. (See "Overview of herbal medicine and dietary supplements" and "Hepatotoxicity due to herbal medications and dietary supplements".)
Choice of brand — Patients who use herbs often ask their providers what brand should be used. Lack of regulatory reform in the herbal industry makes it difficult for the clinician to provide an informed response. One option is to recommend brands that have been tested by independent sources, such as Consumer Labs, and found to meet minimum quality criteria [26]. For ethical reasons, supplements sold through practitioners' offices or multilevel marketing plans should be avoided.
Children and pregnant or lactating women — Very few studies of herbal therapies have been conducted on infants and children or in pregnant and lactating women [27]. Issues of particular concern include proper dosing in young children and greater susceptibility of fetuses and children to potential contaminants. We therefore discourage the use of herbal therapies in these patient groups.
Specific herbal agents
Butterbur (Petasites hybridus) — Extracts from the root of butterbur (Petasites hybridus) contain petasins, compounds that are believed to possess medicinal properties possibly by altering the leukotriene pathway [28]. A systematic review of small, but randomized trials comparing herbal therapies with either placebo or active drug found evidence of efficacy based upon six double-blind randomized-controlled trials [24]. In three of these, butterbur compared favorably with standard doses of nonsedating antihistamines (cetirizine, 10 mg daily and fexofenadine, 180 mg daily) [29-31]. Butterbur preparations are available under a variety of brand names.
Multiple portions of the butterbur plant can contain pyrrolizidine alkaloids, compounds that have hepatotoxic and potentially mutagenic and carcinogenic effects in humans [32,33]. At least 40 reports have appeared worldwide concerning hepatotoxicity with use of butterbur [34]. Most cases of pyrrolizidine alkaloid toxicity result in moderate to severe liver damage. Early signs and symptoms include nausea and acute upper abdominal pain, while more advanced toxicity may present with abdominal distension, jaundice, and the development of ascites. In some cases, if the ingestion of the source is not stopped, the toxicity can lead to hepatic fibrosis and potentially fatal cirrhosis. Manufacturing processes can reduce the content of alkaloids and consumers should choose products that are labeled as low in pyrrolizidine alkaloids. However, they should also be aware of this potential hazard and be advised about early symptoms.
Tinofend (Tinospora cordifolia) — Tinofend is an Indian herbal medication containing extract from the stem of Tinospora cordifolia. In a double-blind randomized trial of 75 patients with allergic rhinitis, those receiving T. cordifolia (at a dose of 300 mg three times daily for eight weeks) reported statistically significant improvement in sneezing, nasal discharge, nasal obstruction, and nasal pruritus, compared with those receiving placebo [35]. The drug was well tolerated, although it caused an increase in total blood leukocyte count in 70 percent of patients in the active treatment group, compared with 11 percent of those receiving placebo; a statistically significant difference. This was attributed to a possible "immunostimulatory" effect by the authors. There have been limited reports of hepatic toxicity, although several in vitro analyses performed by a manufacturer were reassuring [36,37].
Cinnamon bark, Spanish needle, and acerola — A combination of cinnamon bark extract, dehydrated Spanish Needle (Bidens pilosa) leaf and stem, and acerola fruit concentrate (at a dose of 450 mg three times daily) was compared with loratadine (10 mg once daily) and placebo in a randomized double-blind crossover study of 20 subjects with allergic rhinitis and sensitization to timothy grass pollen [38]. Subjects took each study medication for two days and then underwent a nasal allergen challenge procedure with timothy pollen, after which nasal symptoms were assessed and nasal lavage fluid was examined for allergic mediators. Only loratadine significantly reduced symptoms acutely during the challenge, although both the botanical product and loratadine significantly reduced nasal symptoms two to eight hours after the challenge, compared with placebo. The magnitude of effect with both treatments was clinically significant. The botanical product appears to inhibit the production of prostaglandin D2 following challenge, which may suggest a steroid-like impact that affects the late-phase response of allergic inflammation. Long-term use has not been studied. This product is commercially available [39].
Benifuuki green tea — Benifuuki green tea is a specific cultivar that is rich in O-methylated epigallocatechin-3-O-(3-O-methyl) gallate or O-methylated EGCG, a compound that has anti-allergy properties [40-43]. In a randomized trial of 51 adults with Japanese cedar pollinosis, one-half of the group was assigned to drink 700 mL of Benifuuki tea daily, while the others drank a tea that does not contain O-methylated EGCG [43,44]. In the group drinking Benifuuki tea, the symptoms of pollinosis were significantly reduced, quality of life was improved, and the seasonal increase in peripheral blood eosinophils seen in the control group was suppressed. Although the effects were not sufficiently large to suggest that the tea could replace conventional therapies, the authors suggested that Benifuuki tea could be a useful adjunctive treatment.
Yupingfeng granules — Yupingfeng granules contain Astragalus membranaceus, Atractylodes, and Pastinaca sativa. In one study, 118 patients were randomized to cromoglycate drops combined with Yupingfeng granules or cromoglycate alone. In the combined group, 92 percent experienced control of symptoms, compared with 75 percent with cromoglycate alone [45].
Ayurvedic herbal mixes — These are discussed above. (See 'Ayurveda' above.)
NASAL SPRAYS, POWDERS, AND OINTMENTS — Nasal sprays containing either dilute capsaicin or inert cellulose have demonstrated efficacy in randomized controlled trials.
Capsaicin (Capsicum annum) — Capsaicin, derived from red peppers, is believed to act in other forms of rhinitis by desensitizing nasal nerve fibers and reducing nasal hyper-responsiveness [46]. In a randomized study of 42 patients with allergic and nonallergic rhinitis, an intranasal solution of capsaicin and eucalyptol (added to reduce the burning sensation that some patient experience with capsaicin) used twice a day for two weeks was compared with placebo [47]. There was a statistically greater reduction in total nasal symptom score, with the greatest improvement in nasal congestion, sinus pain and pressure, and headache, while the reduction in sneezing, rhinorrhea, and postnasal drip did not differ between the active and placebo groups. This product is commercially available [48].
Cellulose powder — The intranasal application of inert, micronized cellulose powder has been proposed to block mucosal allergen absorption. Some products suggest application every three hours. Products are available in many countries [49]. Some efficacy has been demonstrated in a small number of randomized controlled trials [50-53]. The largest included 53 children (ages 8 to 18 years) with birch pollen-allergic rhinitis who were randomized to cellulose powder or a control preparation of lactose powder [52]. Subjects were monitored for symptoms throughout the birch pollen season of one year. There was a significant reduction in total symptom scores from the nose and specifically for rhinorrhea, without adverse effects. However, another randomized trial of 20 subjects with a crossover design found no benefit [54]. This study evaluated patients with seasonal grass or ragweed allergy who were treated with a nasal spray containing cellulose powder or placebo and then nasally challenged. There was no significant reduction in peak nasal inspiratory flow, total nasal symptoms, or number of sneezes.
Cellulose nasal powders have been available for nearly 20 years in some countries (United Kingdom). As far as the author and editors are aware, there are no reports of adverse effects with prolonged use. It seems logical that these products would interfere with the absorption of other nasal sprays used to treat allergic rhinitis, so if symptom control worsens on the combination, then the combination should be avoided.
Allergen-absorbing ointment — Another method of blocking allergen absorption into the nasal mucosa makes use of a petrolatum-based ointment containing long chain hydrocarbons [55]. In a randomized controlled crossover study, 115 adult and pediatric subjects with perennial allergic rhinitis and sensitivities to dust mites and other allergens were assigned to active treatment or a placebo ointment. Ointments were applied three times daily, each for a 14-day period. No other allergy therapies were allowed. There was a large placebo effect, which may have been due to allergen blocking properties in the placebo gel (containing carboxymethylcellulose), although there was a significantly greater improvement in total nasal symptom scores in the active treatment group. Other smaller studies have also shown efficacy with the same or similar ointments [56-59]. However, comparative studies with allopathic treatments, such as intranasal glucocorticoids or oral antihistamines, are lacking.
CAM THERAPIES WITH MINIMAL EVIDENCE OF EFFICACY — A variety of other herbal preparations, homeopathic products, and miscellaneous therapies have been suggested for the treatment of allergic rhinitis or conjunctivitis. However, studies have either been of low quality or failed to show benefit.
Homeopathy — Homeopathy works on the principle of treatment with "similars." The remedies prescribed by homeopathic practitioners are essentially extremely dilute solutions of drugs known to cause the very symptoms that are to be treated. However, some products labeled as "homeopathic" can in fact contain substantial amounts of active ingredients and therefore could cause side effects and drug interactions.
According to the literature reviewed, 3 to 4 percent of CAM users use homeopathy and about 75 percent of patients seen by homeopathic practitioners report symptomatic improvement. However, meta-analyses and systematic reviews have repeatedly concluded that homeopathy is not different from placebo in the treatment of any medical disorder, including allergic rhinitis [60]. (See "Homeopathy".)
Other herbal preparations — Other herbal preparations, for which evidence of efficacy for allergic rhinitis/conjunctivitis is limited or lacking, include quercetin, stinging nettle, Perilla frutescens, gingko, milk thistle, and grape seed extract.
●Quercetin – Bioflavonoids, such as quercetin, have been of interest in the treatment of allergic diseases based upon studies showing that these compounds could act as mast cell-stabilizing agents, inhibiting the release of histamine, interleukin-8 (IL-8), and tumor necrosis factor (TNF), and inhibiting the formation of prostaglandin D2 in a dose-dependent fashion [61]. Quercetin is one of the components of an Artemisia abrotanum intranasal spray that was administered to 12 patients with allergic rhinitis, conjunctivitis, or asthma in a small uncontrolled study [62]. All subjects reported improvement in symptoms within five minutes of application, which lasted several hours. Ocular symptoms also improved with intranasal application. Quercetin is also found in Spanish needle. (See 'Cinnamon bark, Spanish needle, and acerola' above.)
●Stinging nettle (Urtica dioica) – Extracts from the root and leaves of stinging nettle (Radix urticae) have been used to treat allergic rhinitis. A very small clinical effect was noted in one randomized trial [63]. The Latin genus name comes from the term "burn" due to the urticate (stinging) nature of its hairs secondary to the content histamine and other pruritogenic compounds.
Stinging nettle has no known contraindications or drug interactions, although contact with fresh leaves causes allergic type reactions, such as urticaria and burning and itching upon application to mucosal surfaces, and ingestion is known to cause mild gastrointestinal disturbances and rare diarrhea. It is also used homeopathically. (See 'Homeopathy' above.)
●Perilla frutescens – Perilla frutescens is an Asian herb. Two doses of a preparation enriched for rosmarinic acid was compared with placebo in a randomized controlled trial of 29 patients with seasonal allergic rhinoconjunctivitis [64]. A significant difference was seen in quality of life between the higher dose P. frutescens and placebo after three weeks of treatment, although specific nasal and ocular symptoms were not statistically different.
●Eucalyptus – The steam distillation of eucalyptus leaves generates an oil rich in 1,8-cineole. A clinical study showed that five minutes of inhalation resulted in the sensation of cooling and increased nasal airflow [65]. Eucalyptus preparations have been studied as a nasal decongestant during acute infectious rhinitis when applied in conjunction with camphor, menthol, or steam with improvements in symptoms [66].
●Menthol – Menthol can be used as a topical therapy for rhinitis due to its coolant effect. Menthol acts through the menthol and cold receptor "transient receptor potential channel melastatin 8" (TRPM8) in normal human nasal mucosa [67,68].
●Gingko biloba – There are limited studies in support of the treatment of allergic rhinitis and conjunctivitis [69,70] using solutions of gingko biloba extract, although one study did reflect a positive trend for the treatment of allergic conjunctivitis when applying the extract topically [70].
●Milk thistle – Silybum marianum, or silymarin, is a compound extracted from milk thistle. It has antioxidant and antifibrotic properties and has been most extensively studied in the treatment of liver disease [71]. One study showed that subjects with allergic rhinitis treated with cetirizine, who also took silymarin, had reduced symptoms compared with those taking antihistamine alone [72]. However, this herbal agent has been known to inhibit cytochrome P450 2C8 and 2C9, and alterations in drug levels are of a major concern as it has been shown to decrease the trough concentrations of indinavir in humans [73,74]. It is not recommended for the treatment of allergic rhinitis at this time.
●Grape seed extract – Grape seed extract has antioxidant properties and is marketed for the treatment of a variety of illnesses. However, a placebo-controlled study did not demonstrate any positive effect of grape seed extract on the treatment of allergic rhinitis [75].
Laser therapies — Laser therapies deliver light energy to specific targets, including endobronchial tissues, tympanic membranes, blood, and skin. Laser therapy is described with various terms in the literature, including laser ablation, photodynamic therapy (PDT) of bronchial tissue, endobronchial helium-neon laser irradiation (ELI), and laseropuncture (laser acupuncture) [76-83].
There are no controlled trials of laser therapies for the treatment of allergic rhinitis. An uncontrolled series described 42 patients with refractory rhinitis (allergic and nonallergic) who were treated with a single treatment with a diode laser under local anesthesia [84]. Twenty-five reported subjective improvement in nasal symptomatology, especially nasal congestion/obstruction, and positive effects on quality of life, up to six years later. Nonallergic rhinitis has also been treated with laser therapy [85].
Other types of treatments — Several other CAM therapies have been studied in respiratory or inflammatory diseases, but not specifically in allergic rhinitis. These include apitherapy (ie, bee sting therapy), behavior modification techniques, and speleo- or halotherapy (ie, cave air therapy and salt inhalation therapy, respectively). Thus, these are not discussed further.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.):
●Basics topic (see "Patient education: Alternative medicine (The Basics)")
●It is prudent to ask patients about the use of complementary and alternative medicine (CAM) in a nonjudgmental manner because a significant percentage of patients have tried or are actively using these therapies to treat allergic disorders. The lack of well-designed studies makes it difficult for clinicians to recommend CAM therapies with confidence. However, patients who do wish to pursue CAM should consider the financial costs (which may be substantial) and be aware that CAM products are not monitored in the ways prescription medications are. (See 'Overview' above.)
●Traditional Chinese medicine (TCM) includes herbal therapy, acupuncture, massage, and dietary therapy. The use of TCM for allergic rhinitis is reviewed elsewhere. (See "Chinese herbal medicine for the treatment of allergic diseases", section on 'Therapy for allergic rhinitis and conjunctivitis'.)
●Studies of acupuncture for the treatment of allergic rhinitis have shown modest benefit, although it is difficult to estimate the size of the effect in most positive studies. (See 'Acupuncture and acupressure' above.)
●There are several herbal therapies that have demonstrated efficacy, including Ayurvedic mixes, butterbur, and Tinofend. Patients interested in these therapies should become familiar with the reported side effects and understand that these products are not systematically monitored for safety by drug regulatory bodies. We suggest that pregnant and nursing patients be advised to avoid herbal therapies (Grade 2C). (See 'Herbal therapies (systemic)' above.)
●Patients who seek advice about what brand of herbal medicine to use can be referred to independent sources such as Consumer Labs, which tests various brands of herbal therapies for content and quality. (See 'Choice of brand' above.)
●Nasal sprays consisting of dilute solutions of capsaicin have shown efficacy for allergic rhinitis in randomized trials when administered several times daily. (See 'Nasal sprays, powders, and ointments' above.)
●A variety of other herbal preparations, homeopathic products, and miscellaneous therapies have been suggested for the treatment of allergic rhinitis or conjunctivitis. However, studies have either been of low quality or failed to show benefit. (See 'CAM therapies with minimal evidence of efficacy' above.)
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- Schapowal A, Petasites Study Group. Randomised controlled trial of butterbur and cetirizine for treating seasonal allergic rhinitis. BMJ 2002; 324:144.
- Aydın AA, Zerbes V, Parlar H, Letzel T. The medical plant butterbur (Petasites): analytical and physiological (re)view. J Pharm Biomed Anal 2013; 75:220.
- Cao Y, Colegate SM, Edgar JA. Safety assessment of food and herbal products containing hepatotoxic pyrrolizidine alkaloids: interlaboratory consistency and the importance of N-oxide determination. Phytochem Anal 2008; 19:526.
- WHO Pharmaceuticals Newsletter, 2012. No 4. http://apps.who.int/medicinedocs/documents/s19772en/s19772en.pdf (Accessed on January 03, 2013).
- Badar VA, Thawani VR, Wakode PT, et al. Efficacy of Tinospora cordifolia in allergic rhinitis. J Ethnopharmacol 2005; 96:445.
- Denis G, Gérard Y, Sahpaz S, et al. [Malarial prophylaxis with medicinal plants: toxic hepatitis due to Tinospora crispa]. Therapie 2007; 62:271.
- Chandrasekaran CV, Mathuram LN, Daivasigamani P, Bhatnagar U. Tinospora cordifolia, a safety evaluation. Toxicol In Vitro 2009; 23:1220.
- Corren J, Lemay M, Lin Y, et al. Clinical and biochemical effects of a combination botanical product (ClearGuard) for allergy: a pilot randomized double-blind placebo-controlled trial. Nutr J 2008; 7:20.
- Available in the United States as ClearGuard. Information available at: http://www.nutrilite.com/en-us/Science/NHI/BestOfScience/clear-guard.aspx? (Accessed on March 01, 2013).
- Sano M, Suzuki M, Miyase T, et al. Novel antiallergic catechin derivatives isolated from oolong tea. J Agric Food Chem 1999; 47:1906.
- Fujimura Y, Tachibana H, Maeda-Yamamoto M, et al. Antiallergic tea catechin, (-)-epigallocatechin-3-O-(3-O-methyl)-gallate, suppresses FcepsilonRI expression in human basophilic KU812 cells. J Agric Food Chem 2002; 50:5729.
- Maeda-Yamamoto M, Inagaki N, Kitaura J, et al. O-methylated catechins from tea leaves inhibit multiple protein kinases in mast cells. J Immunol 2004; 172:4486.
- Maeda-Yamamoto M, Ema K, Monobe M, et al. Epicatechin-3-O-(3″-O-methyl)-gallate content in various tea cultivars (Camellia sinensis L.) and its in vitro inhibitory effect on histamine release. J Agric Food Chem 2012; 60:2165.
- Masuda S, Maeda-Yamamoto M, Usui S, Fujisawa T. 'Benifuuki' green tea containing o-methylated catechin reduces symptoms of Japanese cedar pollinosis: a randomized, double-blind, placebo-controlled trial. Allergol Int 2014; 63:211.
- Chen Y. Efficacy of sodium cromoglicate eye drops combined with yupingfeng granules in the treatment of allergic conjunctivitis. Eye Sci 2013; 28:201.
- Blom HM, Van Rijswijk JB, Garrelds IM, et al. Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study. Clin Exp Allergy 1997; 27:796.
- Bernstein JA, Davis BP, Picard JK, et al. A randomized, double-blind, parallel trial comparing capsaicin nasal spray with placebo in subjects with a significant component of nonallergic rhinitis. Ann Allergy Asthma Immunol 2011; 107:171.
- In the United States, a product called Sinus Buster is available without a prescription.
- One such product available in the US and many other countries is called Nasal Ease.
- Josling P, Steadman S. Use of cellulose powder for the treatment of seasonal allergic rhinitis. Adv Ther 2003; 20:213.
- Emberlin JC, Lewis RA. A double blind, placebo-controlled cross over trial of cellulose powder by nasal provocation with Der p1 and Der f1. Curr Med Res Opin 2007; 23:2423.
- Åberg N, Dahl Å, Benson M. A nasally applied cellulose powder in seasonal allergic rhinitis (SAR) in children and adolescents; reduction of symptoms and relation to pollen load. Pediatr Allergy Immunol 2011; 22:594.
- Emberlin JC, Lewis RA. A double blind, placebo controlled trial of inert cellulose powder for the relief of symptoms of hay fever in adults. Curr Med Res Opin 2006; 22:275.
- Paz Lansberg M, DeTineo M, Lane J, et al. A clinical trial of a microcrystalline cellulose topical nasal spray on the acute response to allergen challenge. Am J Rhinol Allergy 2016; 30:269.
- A product called "Pollen Blocker" cream is manufactured by Dr. Theiss Alergol and available on line.
- Li Y, Wang D, Liu Q, Liu J. Randomized double-blind placebo-controlled crossover study of efficacy of pollen blocker cream for perennial allergic rhinitis. Am J Rhinol Allergy 2013; 27:299.
- Bufe A. A simple advice for the prevention of pollen-induced allergic rhinitis. Int Arch Allergy Immunol 2000; 121:85.
- Schwetz S, Olze H, Melchisedech S, et al. Efficacy of pollen blocker cream in the treatment of allergic rhinitis. Arch Otolaryngol Head Neck Surg 2004; 130:979.
- Geisthoff UW, Blum A, Rupp-Classen M, Plinkert PK. Lipid-based Nose Ointment for Allergic Rhinitis. Otolaryngol Head Neck Surg 2005; 133:754.
- Passalacqua G, Bousquet PJ, Carlsen KH, et al. ARIA update: I--Systematic review of complementary and alternative medicine for rhinitis and asthma. J Allergy Clin Immunol 2006; 117:1054.
- Weng Z, Zhang B, Asadi S, et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One 2012; 7:e33805.
- Remberg P, Björk L, Hedner T, Sterner O. Characteristics, clinical effect profile and tolerability of a nasal spray preparation of Artemisia abrotanum L. for allergic rhinitis. Phytomedicine 2004; 11:36.
- Mittman P. Randomized, double-blind study of freeze-dried Urtica dioica in the treatment of allergic rhinitis. Planta Med 1990; 56:44.
- Takano H, Osakabe N, Sanbongi C, et al. Extract of Perilla frutescens enriched for rosmarinic acid, a polyphenolic phytochemical, inhibits seasonal allergic rhinoconjunctivitis in humans. Exp Biol Med (Maywood) 2004; 229:247.
- Burrow A, Eccles R, Jones AS. The effects of camphor, eucalyptus and menthol vapour on nasal resistance to airflow and nasal sensation. Acta Otolaryngol 1983; 96:157.
- Food and Drug Administration. Over-the-counter drugs. Final monograph for OTC nasal decongestant drug products. Federal Register 1994; 41:38408.
- Keh SM, Facer P, Yehia A, et al. The menthol and cold sensation receptor TRPM8 in normal human nasal mucosa and rhinitis. Rhinology 2011; 49:453.
- Liu SC, Lu HH, Cheng LH, et al. Identification of the cold receptor TRPM8 in the nasal mucosa. Am J Rhinol Allergy 2015; 29:e112.
- Volkner JH. [Inhalations of extracts from Gingko biloba in vasomotor rhinitis and in the bronchitic syndrome]. Dtsch Med J 1967; 18:527.
- Russo V, Stella A, Appezzati L, et al. Clinical efficacy of a Ginkgo biloba extract in the topical treatment of allergic conjunctivitis. Eur J Ophthalmol 2009; 19:331.
- Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res 2010; 24:1423.
- Bakhshaee M, Jabbari F, Hoseini S, et al. Effect of silymarin in the treatment of allergic rhinitis. Otolaryngol Head Neck Surg 2011; 145:904.
- Toxicity. Milk thistle and indinavir. TreatmentUpdate 2002; 14:4.
- Doehmer J, Weiss G, McGregor GP, Appel K. Assessment of a dry extract from milk thistle (Silybum marianum) for interference with human liver cytochrome-P450 activities. Toxicol In Vitro 2011; 25:21.
- Bernstein DI, Bernstein CK, Deng C, et al. Evaluation of the clinical efficacy and safety of grapeseed extract in the treatment of fall seasonal allergic rhinitis: a pilot study. Ann Allergy Asthma Immunol 2002; 88:272.
- Khmel'kova NG, Makarova VL, Melent'eva EM, et al. [Does laser irradiation affect bronchial obstruction?]. Probl Tuberk 1995; :41.
- Faradzheva NA. [Efficiency of a combination of haloaerosols and helium-neon laser in the multimodality treatment of patients with bronchial asthma]. Probl Tuberk Bolezn Legk 2007; :50.
- Provotorov VM, Chesnokov PE, Kuznetsov SI. [The clinical efficacy of treating patients with nonspecific lung diseases using low-energy laser irradiation and intrapulmonary drug administration]. Ter Arkh 1991; 63:18.
- Zamotaev IP, Mamontova LI, Zavolovskaia LI, Rudakova OM. [Effect of laser acupuncture on the pulmonary vascular resistance in patients with obstructive chronic lung diseases]. Klin Med (Mosk) 1991; 69:68.
- Morton AR, Fazio SM, Miller D. Efficacy of laser-acupuncture in the prevention of exercise-induced asthma. Ann Allergy 1993; 70:295.
- Gruber W, Eber E, Malle-Scheid D, et al. Laser acupuncture in children and adolescents with exercise induced asthma. Thorax 2002; 57:222.
- Esaulenko IE, Nikitin AV, Shatalova OL. [The use of laseropuncture in patients with bronchial asthma and concomitant chronic rhinosinusitis]. Vopr Kurortol Fizioter Lech Fiz Kult 2009; :37.
- Nedeljković M, Ljustina-Pribić R, Savić K. Innovative approach to laser acupuncture therapy of acute obstruction in asthmatic children. Med Pregl 2008; 61:123.
- Tsai YL, Su CC, Lee HS, et al. Symptoms treatment for allergic rhinitis using diode laser: results after 6-year follow-up. Lasers Med Sci 2009; 24:230.
- Sandhu AS, Temple RH, Timms MS. Partial laser turbinectomy: two year outcomes in patients with allergic and non-allergic rhinitis. Rhinology 2004; 42:81.


text:
Dearly, Departed: A Zombie Novel
- United States
- Young Adult Fiction
- English
More informationLove can never die.
Love conquers all, so they say. But can Cupid's arrow pierce the hearts of the living and the dead-or rather, the undead? Can a proper young Victorian lady find true love in the arms of a dashing zombie?
The year is 2195. The place is New Victoria-a high-tech nation modeled on the manners, mores, and fashions of an antique era. A teenager in high society, Nora Dearly is far more interested in military history and her country's political unrest than in tea parties and debutante balls. But after her beloved parents die, Nora is left at the mercy of her domineering aunt, a social-climbing spendthrift who has squandered the family fortune and now plans to marry her niece off for money. For Nora, no fate could be more horrible-until she's nearly kidnapped by an army of walking corpses.
But fate is just getting started with Nora. Catapulted from her world of drawing-room civility, she's suddenly gunning down ravenous zombies alongside mysterious black-clad commandos and confronting "The Laz," a fatal virus that raises the dead-and hell along with them. Hardly ideal circumstances. Then Nora meets Bram Griswold, a young soldier who is brave, handsome, noble . . . and dead. But as is the case with the rest of his special undead unit, luck and modern science have enabled Bram to hold on to his mind, his manners, and his body parts. And when his bond of trust with Nora turns to tenderness, there's no turning back. Eventually, they know, the disease will win, separating the star-crossed lovers forever. But until then, beating or not, their hearts will have what they desire.
In Dearly, Departed, romance meets walking-dead thriller, spawning a madly imaginative novel of rip-roaring adventure, spine-tingling suspense, and macabre comedy that forever redefines the concept of undying love.
From the Hardcover edition.

subset: commoncrawl


text:
Mitt Romney has visited an emergency centre in hurricane-damaged Louisiana, a day after accepting the Republican nomination for US president.
Mr Romney attended a Friday rally with running mate Paul Ryan in Florida before cancelling a campaign stop in Virginia and diverting to the South.
Mr Romney travelled on his new campaign plane to Louisiana, at the invitation of the state's Republican Governor Bobby Jindal.
The two spent almost an hour meeting local officials and first responders on Friday.
"I'm here to learn and obviously to draw some attention to what's going on here," Mr Romney told the governor, "so that people around the country know that people down here need help."
The presidential candidate shook hands with National Guardsman and met residents who had lost their homes in the storm.
"He just told me to, um, there's assistance out there," resident Jodie Chiarello said. "He's good. He'll do the best for us, you know. He speaks to our best interests at heart."
After a review of a few news articles, this one seemed the most informative and objective.


text:
Your driving instructor for Bournemouth areas
Hi and welcome to my website. My name is Alan and I'm a
fully qualified, DSA-approved driving instructor for RED
Driving School. I offer professional driving lessons in Bournemouth as well as in the Poole, Christchurch, Ringwood, Verwood, Ferndown,
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Learning to drive can be challenging. Being nervous or anxious is completely normal, that's why it's so important to have a patient driving instructor. My approach to teaching is relaxed and friendly, making sure you feel at ease at all times. I guarantee reliability and full commitment to each pupil - no car sharing - every lesson is dedicated entirely to you.
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Being with a national driving school, you can be sure that you will not only be learning in a brand new car, but that there will always be a replacement school car available in case anything goes wrong. You'll also have free access to the Road Brain Trainer provided by RED driving school. Of course your lessons will be just as personal and individual as with a local school. And by booking directly with me you can be sure you'll get a reliable instructor.
All the help you need
As your driving instructor, I will help you pass your practical test and your theory test. You will have free access to Theory Test Pro, a website which gives you a vast number of questions and video clips to learn with. So far all of my pupils have had good experience with this service.
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The school car is a Renault Clio. It has dual controls, air conditioning, power assisted steering and everything else you'd expect in a modern car. It's a very good car for learners, as it is easy to handle and comfortable to drive. Please note that this car has a manual gearbox, unfortunately I can't offer automatic driving lessons.


text:
Toxic flame retardants found in 80% of baby products
Eighty percent of baby products contain toxic or untested chemical flame retardants, according to a new study of products such as car seats, changing pads and portable cribs.
One-third of products, which also included nursing pillows, contained a chemical called chlorinated tris, which was removed from children's pajamas in the 1970s because of cancer concerns, though the chemical was never banned, says a study released Wednesday in Environmental Science & Technology.
The Environmental Protection Agency has said there is a "moderate level of concern" about links between tris and cancer, developmental problems, reproductive problems and other health concerns. The Consumer Product Safety Commission also has found that tris "may pose a significant health risk," spokesman Scott Wolfson says.
Another flame retardant, called TCEP, was found in 10 of the nursing pillows tested. California lists TCEP as a carcinogen.
Toddlers have levels of flame retardants in their bodies three times higher than adults, says Sonya Lunder, a scientist with the Environmental Working Group. That's partly because kids spend so much time on the floor, where chemicals can accumulate in household dust, and because they frequently put their fingers in their mouths, the study says.
The Centers for Disease Control and Prevention has found flame retardants in the bodies of 90% of Americans.
The chemicals are an inexpensive way for manufacturers to comply with California's strict fire safety standard, Lunder says. Because California is such a large market, many manufacturers design all their products to comply with its standards. Companies aren't required to label products containing flame retardants, Lunder says.
Others say the new study may overstate the risks.
"Flame retardants are well-studied and provide important fire safety benefits in homes, cars and public areas," the American Chemistry Council, an industry group, says in a statement. Manufacturers' "dual objectives" are to use "the safest possible chemistry to protect families by preventing fires from starting and limiting the spread of fires once ignited."
Gordon Nelson, a professor of chemistry at the Florida Institute of Technology, notes that some of the baby products tested were purchased in 2002, before a common type of flame retardant was phased out. That chemical, PentaBDE, is no longer used in new products.
Last year, California also exempted strollers, infant carriers and nursing pillows from its fire safety standard, Nelson says.
So baby products might appear safer if researchers were to test only products currently sold in stores, Nelson says.
Four brands — BabyLuxe Organic, Baby Bjorn, Orbit Baby and Boppy — say their products meet California's standards without chemical flame retardants, according to a buyer's guide issued with the study.
Posted | Updated


text:
Bobbi's blocks by Bobbi Anderson
Welcome! You are browsing as a guestWould you like to see 4 projects made from this pattern and much more? create a free account What am I missing?
© XRX, Inc.
© jwesley
© XRX, Inc.
Bobbi's blocks
Nine knit blocks assemble into a great blanket for your newest family additions. The blend of stockinette squares and garter half-blocks offer a chance to play with color and a diversion from just knitting squares.
The yarn requirements are:
375 yds of Color A
500 yds of Color B
125 yds of Color C
125 yds of Color D
Yardage numbers above represent total yardage range.
For more information, see: http://www.knittinguniverse.com/knitters/k100


text:
Last night's episode of iMPACT! Wrestling drew a 0.95 (1.0) cable rating, with 1.13 million viewers.
That number is up 7% and 4% respectively from a 0.89 rating and 1.12 million viewers last week.
That rating is slightly up, but with the question that has been repeated numerous times and given numerous answers, what can tna do to get higher ratings like 1.5 and up on a regular?
It's not anything they can do on screen. To ask that would be to say they havent given us mostly good shows throughout the whole 2013. When we talk ratings we can't always talk on screen. Just because ratings doesnt budge dont mean on screen isnt good. It's more of a network, advertising, marketing and budget problem. Stuff that obviously nobody can do anything about or they would have already. Like Hulk and Eric said in their canada q and a…. TNA needs Dixie's daddy to give them some more money. Thats not gonna happen so they press on as is.
More money isn't the problem… You don't sink more money into something that isn't working. It's partly the fact that TNA has little to no advertising in their budget, they overpay wrestlers like Hogan quite often. They spent far to much going on the road, when that money could've been used for advertising.
Also yes, the on screen product has been going downhill. I find the matches have become more just tossed together for giggles without anything behind them. While the matches themselves are good, they lack any real reason to watch unless you're a hardcore wrestling fan. You can also tell the moral for the wrestlers is down significantly, as the quality of some of the work has been going downhill compared to their past work.
Get used to TNA being the little dog for a looooooooooooooooooooooonnnnnnnnnnnnnnnngggggggggg time. We might be dead or elderly before they become a true big dog. We are first gen TNA fans. It'll take way more ppl to be raised on TNA to help. Plus dont forget WWE ratings are not what they were either. Wrestling isnt as popular as it once was. WWE is viewed as wrestling. So people who wanna see wrestling will pretty much only watch WWE. Wrestling is that thing that WWE does in America's eyes
Most current TNA fans are at least 2nd gen fans. TNA lost at least half of their 1st gen fans that were into the amazing KO's division and X Division of the past. TNA may have picked up SOME new fans during the "Hogan Era," but they lost just as many as they have gone more in a "sports entertainment" direction with their product, rather than the "wrestling" product of the past.
like i said on here before. reading about the ratings is kind of pointless. it either up a little or down a little. it nothing new and something that will surprise us.
until they have better marketing
Rewind a couple of years and everyone was swearing that Hogan was going to bring TNA 3+ ratings. Oh how times have changed. Going live on the road didn't produce any real bump either. I really wish TNA could get over the hump but after so many years I don't see it happening. Spike tv isn't exactly the USA network but it's not chump change either. What options are available? A jump to TBS/TNT?
i dont think many other networks will jump at a shot at tna. plus with how things are in the wrestling world. tna better off with spike who will do anything to keep them. spike not the best place for tna but it all they got at the moment.
Back when they first announced going on the road, I said it would be financially disastrous and wasn't going to work. They've gone on the road before this, and it never did anything for the ratings… The only difference this time around is that they spent far more than ever before.
TNA was foolish believing Hogan would do much of anything… He's known for his time in WWE during the 90s and always will be; he's irrelevant to anything in the industry now. Fans aren't going to watch the product just because of him, and most fans under the age of 23 or so barely know who he is, nor do most of them care.
Keep Bully as champ.. Dude owned it on Thursday. Hairs on my neck stood up, hasn't done that for a while. He looked like a beast. He is a beast. Until someone can challenge him on the mic why change. Keep the story ticking with a guy at the top of his game.
This isn't going to happen, the story is heading towards A&8s members costing him the title at B4G.
I 100% agree with you.
Currently, he is unparalleled in TNA. As much as I like AJ Styles (he is actually my favorite wrestler), he was trumped by Bully Ray, making him look ridiculously green. Outclassed is a word that comes to mind. There was a moment when Bully covered for him because Styles did not realize that he should have jumped in with some heat back at Bully. "Whatsa matta, you aint got nuttin to say?" Bully then got the dead crowd behind AJ when he wanted to quiet everyone from chanting "AJ".
Bully Ray is the epitome of a professional.
I do want to see the strap on AJ, but if you are looking for someone to rival Bully on the mic, you may need to look into people like Aries, Anderson, Roode, Daniels, Angle, or Storm (Even Kenny King looks promising). Don't get me wrong, AJ is "decent" on the mic, but when you pit him against someone like Bully, he will be overshadowed every time.
How can I forget Joe?
Agreed. But Aj is the man that puts butts in seats. Whether his promos are good or bad, people live through him. Like hogan and Austin. Plus he is legitimately arguably better than punk and Bryan
Uh… Your hair stood on your neck?? Wow…did your peckar get hard too….u truly are a joke…and a hamster….
Did you hear something? Must be trolls under the bridge, nevermind.
in comparison, tna has remained rather steady in the ratings compared to raw. The wwe has recently started to put out a fantastic raw product (in large part thanks to hhh's work with nxt and the tag team division). I think there is a boom period to come soon if tna can hold on.
I am affraid the attitude era fan in me has been won back to wwe now with Wyatt family, Fandango, Shield, Ziggler, Usos, Los Mantatoros, Orton, Bryan, Bellas, Punk, Heyman, Axel, AJ Lee, Steph and HHH, Cody, RVD, Big E… There isnt a dull moment in 3 hours of television. All they need now is time to develop stories with the talent.
tna needs to concentrate on slowing down entrances, giving them cool themes like AJ, Storm and Roode, simplifying matches (i.e. less ref bumps, less tearing the ring up for the sake of it), just put out a solid product and get that 'buzz' by having 4 off the charts ppvs with 5 star unpredictable matches and surprise signings etc.
TNA don't have the luxury to slow entrances down, they don't have enough tv time as it is. I will take your word for it that Raw is getting better, I gave up on it a long time ago. From what I seen no one can hold a candle to Bully.
Give it a watch purely for bray wyatt (husky Harris). Insanely good gimmick promos and entrance.
Also 2 hours is a long time. Everyone needs a decent entrance to put over their personality, it's half the game really. Hhh, rock, taker, Kane, Austin, dx, nwo, wyatts, hardyz, new age outlaws, brood, usos, y2j, Aj styles (note only tna guy mentioned)… All had memorable entrances and defined their characters.. If I'm just tuning in, I am not excited or intrigued when Magnus comes out. Not having a go, just saying
about a hour twenty without ads. Entrances are important, but also cost more money, Pyros etc. I think Mr Andersons entrance is gold. In ring entertainment is more important than getting there but I get you point.
Well Sturk, WWE is more about entertaining than Wrestling. I think TNA is still is more of wrestling tradition than WWE is, i think you got that backwards there.
Wrestling as a whole has been taking a hit


text:
As an old-timer myself, it's time we say "you're special" to people have been working at exactly the same place for 40 years or more. Today, I'm beginning a series on people who "stay put" with the same employer for four decades or longer. The columns on these long-timers will appear on occasional Wednesdays. Call me with suggestions at 563-383-2249 or
email@example.com or by mail at 500 E. 3rd St., Davenport, Iowa 52801.
At the age of 18, Mary Hasson had just graduated from Davenport West High School and taken a job as a server at Riefe's Restaurant in Davenport. Her intent was to stay a few years until going to college.
It is 40 years later. Mary is still at Riefe's. She has never worked anyplace else and would never think of switching jobs.
"They can call me a server," she says with a bossy smile, "but I'm still a waitress to my customers. I love them all."
They love her, too, especially when she bakes an apricot pie at home for someone, or on Wednesdays, when she makes a pan of bread pudding for customers.
Mary earned her bachelor's degree in history at the former Marycrest College, all the while working nights full-time at Riefe's.
"It's more fun here than working at some place like a museum," she says.
Mary is so devoted to her job and her regulars that when she recently marked her 40th year at the northwest Davenport restaurant she brought two sheet cakes as a personal celebration.
Mary is flitting around like a bumblebee while we visit. She's back and forth, working tables and sitting down — a few minutes at a time — to talk about her 40 years serving tenderloins and frog legs and fried chicken and hot pork sandwiches.
"She's absolutely amazing," says Dan Riefe, one of the owners of the place. "She's ahead of the customers, filling up their coffee cups before they're half empty. I really believe that she could serve this whole place by herself."
After 40 years on her feet — which, she says, never get sore — Mary has tales to tell.
"Once I dumped a chocolate soda over three executives from Northwest Bank," she says, trying to keep from laughing. "But my worst was when a customer brought in one of those big Dairy Queen birthday cakes. It was to serve 10 or 12. I had it on a tray and it slipped from the tray to the booth and then to the floor. I wanted to hurry out and get another one, but they said no. They picked it off the floor and ate it."
When Mary started at Riefe's in 1972, her pay was $1 an hour. Coffee was 15 cents a cup. "Plus one-cent tax," she quickly says. In those days, servers wore white dresses and hair nets. Now, it's black slacks, and she doesn't recall when they quit hair nets.
Dan Riefe joins us in a booth with a
calculator to figure out how many customers Mary has served in 40 years. He says the numbers show that Mary has served at least a half-million patrons.
"It's been a good living. A server can make good money. Tips are better since I began. Customers are more big-hearted. I once got a $50 tip," she says before dashing off to tend to another table.
"It's been an interesting life, too. I've seen changes. Customers are more picky now than when I began. Healthier foods, vegetarian meals, that sort of thing."
Mary works the night shift, and after 40 years, she shrugs: "Why quit now? The Riefe brothers (Dan and Rick) are wonderful bosses, I think I'm good for another five years."
Many of her customers have been with her for much of her career.
We have to quit talking. Another table has just been filled, but Mary steps aside to wave goodbye to Dick and Jan Kluger. They have had their evening meal with her for as long as she can remember.


text:
I have a Canon camera. I have tried uninstalling a Canon program from the
control panel. It will not uninstall. I have tried using the uninstall.exe
from the Common Files/Canon. It won't uninstall. Canon couldn't help me at
all. We tried several different things, even a system restore. Nothing
works. Any suggestions?


text:
by Staff Writers
Wallingford CT (SPX) Jun 19, 2013
Mutualink has announced the deployment of the Global Secure Emergency Collaboration Network (GSEC Net) for multinational events and emergencies. GSEC Net is a new, always on, secure global interoperable communications platform that enables nations and their agencies to seamlessly communicate and collaborate with other nations as and when needed in response to events wherever they occur.
GSEC Net is being utilized by the U.S. Department of Defense (DoD) during a month-long global exercise based at Aberdeen Proving Ground (APG), Maryland in coordination with the Rio de Janeiro Integrated Command and Control Center in Brazil, and a host of other participating nations, including Columbia, South Africa, Canada and Belgium.
Through Brazil, GSEC Net will facilitate interagency and multinational communications for major international events including a Papal visit next month, the 2014 World Cup and the 2016 Olympiad, providing a virtual multinational global emergency operations center capability.
Mutualink's GSEC Net is an innovative platform that enables national partners and their agencies to seamlessly bridge communications and share real-time multimedia information on a global scale. GSEC Net is an always on, always available platform that can be leveraged for planned activities, as well as for managing unexpected crises requiring international coordination.
GSEC Net is a global extension of Mutualink's IRAPP (Interoperable Response and Preparedness Platform), which is deployed by hundreds of public and private entities throughout the United States. GSEC Net utilizes the same innovative peer network and has no central switch architecture, eliminating security issues and the requirement for national resources to be controlled by a third party.
Each participant maintains sovereign control over its communications and information assets. A nation who joins the GSEC Net in preparation for an upcoming event remains persistently connected to the network as world events shift around the globe.
Communications on GSEC Net are end-to-end encrypted using AES 256-bit encryption ciphers and are mutually authenticated through encryption keys. GSEC Net is non-proprietary and open-standards compatible, as well as being network and device agnostic. The network is cost-effective and simple to deploy.
GSEC Net Deployed for Military and Defense
Locations using Mutualink include U.S. military bases and entities, as well as sites in Brazil, Colombia, South Africa, and the 28 Nations of NATO via deployments in NATO Special Operations installations in Belgium.
To demonstrate the effectiveness of the GSEC Net, a simulated incident will take place in Brazil involving citizens from multiple countries. All of the nations whose citizens are affected will be alerted in real time to the emergency response status with key information being exchanged regarding situation status as the situation unfolds.
"With the instant situational awareness and collaboration that GSEC Net affords, global partners are able to effectively monitor, assess and respond in real time to international events that may affect their citizens at home or abroad," said Joe Mazzarella, Senior Vice President, Mutualink.
"There's an increasing need for interoperable communications capabilities on a global scale so that nations can work together quickly and effectively, irrespective of where and when events occur."
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text:
So while the holiday drinks are flowing ever faster, I thought I would put up the expected calorie load of these bad boys that have been pouring out of the shops for the last few weeks. Don't want to rain on anyone's Christmas parade, but I thought it would be best to be an educated consumer.
Calories in specific drinks (For Starbucks: no whipped cream and whole milk):
Starbucks Eggnog Latte
Grande: 424 calories, 21g of fat
Venti: 530 calories, 26g of fat
Starbucks Gingerbread Latte
Grande: 336 calories, 13g of fat
Venti: 420 calories, 16g of fat
Starbucks Peppermint Mocha Latte
Grande: 368 calories, 12 g of fat
Venti: 460 calories, 15g of fat
Dunkin Donuts Gingerbread Latte
10 ounce: 400 calories, 9g of fat.
For reference: McDonald's Quarter Pounder, no cheese: 420 calories, 21g fat.
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I know some people are freaking out, but I'm surprised at how LOW the caloric value for these drinks are.
For reference: Jack in the Box
Egg Nog Shake 16oz 870 Calories!
Egg Nog Shake 24oz 1310 Calories!
(source jackinthebox.com)
Note to all you holiday dieters out there: CHILL.
Your body burns about 12 calories per pound of your body weight in order to run vital organs without exercise. Just manage how you spend them.


text:
Sally's Recipe of the Week: Hog Snapper with Acorn and Apple Pure
Hog Fish with Acorn Squash and Apple Pure
Ingredients For Fish
Kosher or sea salt
Black pepper
1 and 1/4 pounds of Hog Fish or Snapper fillets
1/3 cup all-purpose flour
6 tablespoons unsalted butter
2 tablespoons lemon juice
2 tablespoons chopped fresh parsley or chives -optional
Ingredients for Pure
2 Acorn squash
2 apples, peeled and diced
4 tsp butter plus 3 TBS unsalted butter divided
2 shallots, chopped
chicken stock
Salt and Pepper
Preheat the oven to 350 degrees F.
Place the squash halves, cut sides up, in a large baking dish. Place 1 teaspoon of the butter in the center of each squash. Sprinkle the insides lightly with the cinnamon and nutmeg. Add enough water to cover the bottom of the pan by about 1/4-inch (about 1/2 cup), cover tightly with aluminum foil, and roast until the squash is tender, 50 minutes to 1 hour.
Remove the squash from the oven, uncover, and let sit until cool enough to handle. Using a spoon, scoop the flesh from the squash into the bowl of a food processor.
Melt 3 tablespoons butter in a medium skillet over medium-high heat. When the butter is foamy, add the shallots and cook, stirring, until soft and fragrant, 45 seconds to 1 minute. Add the apples, salt, and pepper and cook, stirring occasionally, for 3 minutes. Add the stock and cook, stirring occasionally, until the apples are very tender, 8 to 10 minutes.
Remove the pan from the heat and transfer the apple mixture to a food processor with the squash. Puree the mixture on high speed until smooth. Adjust the seasoning, to taste, and keep warm.
Wash the fish fillets and pat dry with a paper towel. Season the fish fillets to taste with salt and pepper. Heat a large sauté pan over medium-high heat. Add three tablespoons of butter to the pan and swirl around until the butter is melted and the foaming subsides.
Dredge the fish in the flour, shaking off any excess and immediately place in pan. (Don't dredge fish and then let them sit for a while makes them mushy.
Cook the fish for three to four minutes (the underside should be golden-brown), then carefully turn over. Bring the heat down if it is cooking the outside too quickly. Cook for an additional three to four minutes, then move the fish to a plate and keep warm with a foil tent.
Lower heat and add remaining butter to the pan. Cook until the melted butter turns a light brown. Add lemon juice and parsley. Cook for a few seconds more.
Divide the pure evenly on plates, place fish on pure, pour your lemon juice mixture over the top and serve immediately.


text: Hello: The problem with the simple instrument tracks is a SOnar bug that hopefully will be adressed in a future update. In order to remove a component of a dimension program, you'll need to find out which element has the sound you want to remove by choosing each of the mixer parameters for the four elements and muting them until you mute the one you want, then save it as a program with a new name. Gord ----- Original Message ----- From: blue wings To: ddots-l@xxxxxxxxxxxxx Sent: Sunday, April 26, 2009 5:16 AM Subject: [ddots-l] A few questions Hi I have few questions :) When I choose the simple instrument track in sonar and next choose some effect I dont see the parameters of this effect in the track inspector, where is the problem? My second problem is the problem with the dimension pro, I like one of the presets, but there is a problem. In this preset there are 2 sounds, the piano and some strange sound. I dont like this second sound, but I want to use the first one. Is there any way to eliminate this second sound, or maybe anyone know some sound which is similar to the first sound of this preset. The sound which I meen is alien piano 2 or 3. I want also know how to put the hsc set for fm7? And also, is the omnisphere accessible for us. And my last question, how to lock the mouse in sonar? :) cause I forgot how to do it. Regards, Ralf.


text:
By JON LANCE
News-Telegram Staff Photographer
Hopkins County Community Chest is in for some big changes this year thanks to Lowe's Home Improvement Store and Hopkins County Emergency Medical Services.
First, on June 25, Lowe's Distribution Center in Mount Vernon collected approximately 2,000 pounds of food donated for the community chest during a drive at the warehouse
"The food donations from that facility are huge for us," said Judy Ann Moore, executive director for the Hopkins County Community Chest. "But, that donation was just the first in a saga of wonderful things that has happened here recently at the food bank."
Second, Hopkins County EMS is hosting a "Strike-Out Hunger" Softball Tournament at Coleman Park Saturday, July 26. A team entry fee is $200 or the equivalent in canned food. The deadline to sign up for the softball event is July 23. Lowe's will be donating a hot dog stand, tent and food for the event. All proceeds from the food sales and game will go directly to Hopkins County food banks.
"We are so thrilled for the upcoming softball event," said Moore. "We really need the resources to help feed our community."
Third, Lowe's is also sponsoring a free dinner for food bank clients on Aug. 7. The meal will be at First United Methodist Church; the time will be announced closer to the date. Moore invites anyone in the community who is in need to dinner that evening.
"Lowe's is going to cook the meal, serve it and everything else that evening," stated Moore. "Lowe's wants to help the community and enlighten their staff that there are real hunger issues in East Texas."
"The people who are struggling with hunger in our community are individuals most people would be shocked to learn need food assistance; 18 percent of our clients are grandparents who are guardians of their grandchildren."
Fourth, and perhaps the biggest change for the community chest, will be a completely redecorated warehouse with new storage units, lockers and a "county store" — all made possible by Lowe's.
Since Moore took over the community chest last year, she has wanted her clients to choose their own food instead of distributing pre-made bags that may not coincide with recipients' dietary restrictions. That's where the idea of the "country grocery store" started to take shape.
"Right now, if one of our clients has diabetes or food allergies, they have no control over what they are given at the pantry," Moore said.
Lowe's will be redesigning the community chest distribution center to resemble a traditional "grocery store" with aisles and grocery carts. Individuals who are on the food pantry member registry will receive a list at the front of the store with a specific number of fruits, vegetables and meats they can select based on their family's size. They then walk the aisles of the community chest and select anything they want in each category on their list.
At the end of the checkout process, someone from community chest compares the number of items the recipient has with the list to make sure they match; when they do, the items are packaged for the recipient to take home for their family. A volunteer from the community chest will even help them load the food into their vehicles, if needed.
"We wanted not only the freedom of choice to be apart of the community chest but personal dignity," said Moore.
Construction on the "country store" is expected to be completed in August.
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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (
The Natural resistance-associated macrophage protein 1 (Nramp1 or Solute carrier 11 member 1, Slc11a1) transports divalent metals across the membrane of late endosomes and lysosomes in professional phagocytes. Nramp1 represents an ancient eukaryotic cell-autonomous defense whereas the gene duplication that yielded
Nramp was identified by positional cloning of the dominant gene responsible for the macrophage quantitative trait of natural resistance to infection by unrelated bacterial and protozoan pathogens [
Nramp proteins are classified as Solute carriers 11 (Slc11) that mediate chemiosmotic uptake of divalent metals such as ferrous iron (Fe2+) and manganese (Mn2+) [
Bacterial Nramp homologs function as proton-dependent Mn transporters (MntH) but display polyphyletic origins that suggest derived evolution. One group of MntH sequence is restricted to anaerobic micro-organisms; another group possibly emerged later is widespread among Bacteria and includes Archaea, whereas the third group was apparently derived by horizontal gene transfer from a eukaryotic source and is more prevalent among bacteria associated with eukaryotic cells [
In contrast,
Nramp1 (Slc11a1) was characterized as a divalent metal importer expressed specifically in the membrane of late endosomes/lysosomes of professional phagocytes [
The gene duplication that yielded
The coelacanth diverged early from the Sarcopterygian lineage (most ancient specimens found ca 420 million years ago, Mya) [
Phylogenetic distribution of
Iron deposition into mature enamel is important for tooth constitution and Fe is the only element detected as deposited by ameloblasts outlining the enamel surface of the teeth [
In bony fishes, Fe concentrations in the enameloid were related to the phylogeny of fish and it was proposed that the mechanism of Fe concentration appeared early and disappeared later in the course of fish evolution [
It might thus be suggested that ensuring novel house-keeping functions such as iron deposition in dental enamel contributed to maintaining both
The professional phagocyte phenotype of natural resistance to infection by intracellular pathogens which is shared by mouse macrophages [
In general, immunity to mycobacterial species depends on the activation of macrophage microbicidal activities through the IL-12/IL-23–IFN-γ axis. Genetic deficiencies in
Strong evidence supports a critical role for genetic factors in susceptibility or resistance to TB but the mechanisms involved remain elusive. Host resistance to TB is a complex trait due to an intricate balance of host-Mtb interactions involving multiple genes and compounding factors (e.g., phenotype definition, study design, human and microbial population genetic heterogeneity and linkage disequilibria, socio-economical determinants, environmental factors such as nutrition, co-infections, epigenetics, ...). TB resistance has been associated with several gene polymorphisms but with low consistency between replicate studies, while most clinical association results are not yet validated functionally by molecular studies [
Genetic variants under evolutionary selection often have accumulated to relatively high frequencies, which might represent an equilibrium between benefits procured for TB resistance and high risk of other diseases, such as adverse consequences of microbicidal activities [
Polymorphisms at the 3' end of
In few instances
Soon after invading macrophages
Hence, several
Z-DNA formation can facilitate transcriptional initiation and activation. This left-handed conformation of the double helix may be formed at TG repeats within promoters upon remodeling of a mononucleosome by the human SWI/SNF complex [
Alleles other than allele 3 were significantly associated with an increased risk of TB, independent of disease type, with a meta-analysis mean odd ratio of 1.31 comparing cases to controls (95% confidence interval: 1.59–1.08) [
The hypoxia-inducible factor alpha (HIF-1α) represents a strong candidate transcriptional activator binding at
HIF-1α is key for M1 microbicidal macrophage functions since HIF-1α basal activity can be stimulated in non hypoxic conditions by a variety of compounds such as growth factors, cytokines, nitric oxide, LPS and a range of infectious microorganisms [
Current genetic data thus suggest that
A hallmark of
The myeloid lineage is part of the haematopoietic system which comprises blood cells and is organized hierarchically. Under the current paradigm of hematopoietic differentiation blood cell types arise from hematopoietic stem cells (HSC) which can self-renew or evolve through multiple progenitor and intermediate maturation states into 12 terminally differentiated cell types [
Control of
mRNA profiling of intermediate and terminally differentiated cell types revealed that genes are tightly coexpressed in modules which are restricted to specific lineages or common to multiple hematopoietic lineages and interconnected. Five dominant phenotypes: HSPCs, differentiated erythroid cells, granulocytes/MNs, B cells and T cells are distinguished by a set of differentially expressed genes specific to each lineage as compared to the others [
Vitamin D active metabolite ((1α,25)OH2 VitD3, VitD) binds the vitamin D receptor (VDR) and the VitD-VDR complex assembles with the retinoic X receptor (RXR, which binds 9-
Retinoids do not induce
The regulation of
Local productions of VitD by epithelial and immune cells as well as adipocytes exert autocrine or paracrine immunomodulating effects [
This paracrine antimicrobial role of VitD is required for IFN-γ-mediated microbicidal activity of human macrophages. TH1 cell-secreted IFN-γ induces VitD antimicrobial pathway (cathelicidin and β4 defensin peptides, CYP27B1 and VDR), which is similar to the response triggered by TLR2/1 ligands (e.g., Mtb-derived 19-kD triacylated lipopeptide). Both rely on monocyte secretion of IL-15 albeit through different pathways (STAT1 or MyD88). Monocytes stimulation by IFN-γ depends on the presence of sufficient VitD serum precursor as IFN-γ stimulates CYP27B1 activity and treatment with IFN-γ is inhibited by a VDR antagonist. In addition, IFN-γ-induced autophagy and phagosome maturation are VDR-dependent. A concentration superior to 45 nM of 25OH VitD3 is strictly required to observe IFN-γ—and IL-15-dependent monocyte antimicrobial responses (autophagy, antimicrobial peptides). VitD appears thus instrumental for acquired immunity to activate macrophage antimicrobial responses that overcome intracellular pathogens evasion strategy [
In HL-60 promyelocytic cells, inducing differentiation with VitD was required to obtain upregulation of the accumulation of the endogenous
During differentiation various epigenetic marks decorate the genome to demarcate domains of activity that are affected in a hierarchical manner. For instance, HSC pluripotency genes get progressively turned off with the onset of differentiation, by recruiting histone deacetylases and affecting histone methylation pattern to induce formation of heterochromatin [
Several members of the C/EBP family of bZIP transcription factors have important roles in myeloid development, and in macrophage in particular, as C/EBPα , C/EBPβ and C/EBPδ represent three of the 18 regulators most frequently represented in the 14 modules enriched for macrophage-related gene signatures [
C/EBPβ (a.k.a. NF-IL6) is a key regulator of monocytic cells development [
Regarding macrophages,
The contribution of the Specificity protein 1 (Sp1) to regulate
Progress in understanding molecular mechanisms of
In the days following PMA-induced differentiation of HL-60 cells, β-actin translocates from the cytoplasm to the nucleus in a process that requires p38 MAPK activity [
The Activating transcription factor 3 (ATF3) is a member of the ATF/cyclic AMP responsive element binding family (CREB) family of transcription factors. ATF3 is expressed in a number of splice variants and interacts with multiple partners to form dimeric complexes, acting either as repressor or activator of various genes. For instance in Toll-like receptor (TLR)-activated macrophages, ATF3 recruits the histone deacetylase 1 (HDAC1) to the promoters of genes encoding cytokines or involved in metabolic and inflammatory responses, exerting negative regulation by epigenetic modification [
The recruitment of β-actin to
Induction of
HSC differentiation results from a stepwise process that produces cells demonstrating various degrees of lineage potential until reaching a stage of committed progenitor, which yields only one lineage through a multistage process producing mature cells. Because most eukaryotic DNA is packaged in closed, tightly packed chromatin conformation (heterochromatin), chromatin structure has an important role at the local and chromosomal levels in controlling hematopoieteic gene expression by regulating accessibility to the transcription machinery [
Using the University of California Santa Cruz (UCSC) Genome Browser [
Transcriptional activity at
A single predicted transcription start site (SwitchGear Genomics) locates 41 bp downstream the major TSS mapped experimentally [
Substantial overlap between the sequence segments obtained by either enzymatic digestion of open chromatin or mechanical fragmentation based on specific interaction with nuclear proteins hence suggests candidate regulatory factors
Among the 50 DNAse I footprints examined over the selected 76,543 bp DNA fragment that spans from
The interval covering
Nucleosomal remodeling at
This area is also covered by a larger DNA segment that was reported by ChIP-Seq analysis of HepG2 cells, after immuno-precipitation using antibodies specific for C/EBPβ followed by high throughput sequencing, suggesting that in HepG2 nuclei
One of the signals found selectively in myelo-monocytic nuclei constitutes the C/EBPα/β binding site at
These footprints at sites distant from
No candidate transcription factor has yet been identified by ENCODE ChIP-Seq analyses for the remaining four DNAse I footprints selectively found in myelo-monocytic background (CD14+ MNs, HL-60 cells, ~18 and 10 kb upstream of
Another hypothetical C/EBPα/β site further upstream is flanked by a 3' binding site for the Signal transducer and activator of transcription 3 (STAT3), which are predicted on similar grounds (DNA sequence fragments hypersentive to DNAse I matching those pulled by ChIP-Seq assay): both candidate sites are covered by a 410 bp genomic footprint; the DNA fragments pulled down by ChIP-Seq share the 5' boundary but STAT3-specific segments extend 150 bp further in 3'. This upstream C/EBP site is equally associated with C/EBPβ and PU.1 both in CD14+ MNs and MDMs (
Mobilization of
These two predicted C/EBP sites ~400 bp distant differ in occurrence among cell types. The more upstream region that can interact with STAT3 and C/EBPβ was sensitive to DNAse I in 65 cell types, giving intense signals in MNs, HL-60 and NB4 (by decreasing order; Footprint #5,
STAT3 and C/EBPβ have complementary roles supporting host defense against infection as both are IL-6-regulated transcription factors [
The long isoform MAFB induces monocytic differentiation [
Candidate transcription factors are suggested for one of them: a 210 bp DNAse I sensitive fragment closely overlaps with three DNA segments recovered independently by ChIP-Seq which bound PU.1, EGR-1 and USF1 in the chromatin of megakaryocytic K-562 cells. The megakaryocytic lineage constitutes a myeloid sister group of the myelo-monocytic lineage (
The upstream stimulatory factor (USF1) is a ubiquitous c-Myc-related regulatory factor required for M6PR promoter activity [
This candidate 5' distal myeloid
ELF-1 and PU.1 belong to the same family and ELF-1 is also known to contribute enhancer activities [
Based on currently known DNA-protein interactions at
Few other DNAse I footprints within the CTCF boundaries of
About 2 kb downstream of
Two other elements potentially important for
To confirm the existence at
Another myeloid lineage is represented by CMK cells, human acute megakaryocytic leukemia (M7) cells derived from a patient with Down syndrome. CMK cells differ from the chronic myeloid leukemia (CML) in myeloid blast crisis K-562, as the former exhibits more megakaryocytic properties and the latter erythroid markers [
In summary, combined examinations of DNAse I footprinting and ChIP-Sequencing converge to reveal different types of protein-DNA interactions. Depending on cell type(s) in which they were found these DNA-protein associations may occur at different stages of, or be maintained through, the myelo-monocytic differentiation program. Data indicate that
Alterations of chromatin structure, such as changes in nucleosome positioning and histone-modification patterns contribute to regulate gene transcription [
Hence myeloid specificity of
The gene flanking
A more detailed appraisal of local histone modification landscape and that includes nuclei of CD14+ MNs provides crucial information to delineate areas of myelo-monocytic specific transcriptional activity and compare these with DNAse I footprinted regions (
The 5' boundary of
The marked region that overlaps the first half of
The downstream area located close to the end of
The fourth small region matches a footprint that was detected in MNs, whose position corresponds to a potential C/EBPβ site detected by ChIP-Seq in HepG2 cells upstream of the TSS (DNAse I Footprint #7,
In comparison, in megakaryocytic cells the upstream region is partially marked, slightly at the 5' boundary and more strongly in its middle; also the third, downstream region is well marked at the 3' end (both regions bear strong H3K4me2 and H3 ac marks suggestive of enhancer activity,
In HepG2 cells, the ends of the upstream region are marked lightly as well as the downstream 3' region (H3K4me1,2,
To study further
The data suggest that histone modifications observed in K-562 megakaryocytic cells (H3K4me1-3; H3K9ac and H3K27ac) and in NB4 promyelocytic cells (H3K4me3), as well as protein interactions revealed by ChIP-Seq analyses at relevant DNA sites and involving RNA Pol II, c-Myc and Max (
Interestingly, another myeloid pathway, erythroid differentiation, stimulates the expression of transferrin receptor 1 (TfR1) and ferrochelatase (Fech) and increases iron uptake and heme biosynthesis as a result of more c-Myc-Max functional complexes interacting with TfR1 and Fech promoter elements [
Histone modification pattern indicates
In another set of data, weak association of C/EBPβ with one of
The predicted
In MNs, histone modifications extend towards both ends of a large regulatory domain. In the 5' half and at the 3' end, H3K4me1,2 and H3K27ac marks dominate suggesting myelo-monocytic specificity whereas most of the 3' half, which is marked also with H3K4me3 and H3K9ac, rather indicates more common regulatory elements (
In addition, ChIP-Seq analyses of RNA Pol II distribution demonstrate several interactions with relevant DNA segments in HL-60 cells (
Current data on
Compared to NB4 cells HL-60 chromatin state shows differences which could be due to heterogeneity among APLs. Differential pharmacological modulation of histone modifications have previously been reported with NB4 and HL-60 cell lines; such as H4 acetylation in the G-CSF receptor promoter at the C/EBPα binding site in HL-60 but not in NB4 cells [
The data raise the possibility that
In contrast, the central core element of this large 5' enhancer corresponds to a common DNAse I footprint (121 cell types) which matches DNA fragments pulled by ChIP-Seq that targeted a variety of transcription factors, including RNA Pol II, c-MYC-MAX, EGR-1, ETS-1 and ELF-1. These factors are similar to those potentially binding at the 5' boundary of this large enhancer element, as well as at
In MNs, histone modifications around
The H3K4me3 mark indicative of transcriptional activity shows conserved pattern in PBMCs (
The last element identified represents a distal promoter constituent that likely interacts with C/EBPβ , and preferentially in mature myelo-monocytic cells (Footprint #7,
Comparing NAS-Seq data from CD34− monocytic cells and their CD34+ HSC progenitors (EIO-JCVI NAS) [
Lastly, the chromatin state of non-hematopoietic hepatocellular carcinoma HepG2 cells demonstrates low level transcriptional activity (ENCODE Caltech RNA-Seq,
Combined chromatin signatures and association with RNA Pol II are highly correlated with enhancer activity [
In addition, K-562 and NB4 cells lack RNA Pol II association at sites corresponding to DNAse I hypersensitive elements in the predicted upstream enhancer element. The more 5' site is found mainly in myeloid cells (11) and the other (65) is more common (Footprints #6 and #5, respectively). The presence at these two sites of c-Myc-Max complexes in NB4 and not K-562 cells may thus be interpreted as myelomonocytic-specific recruitment of a transcription factor, which is one of the first steps of enhancer nucleosome remodeling [
It is thus possible to propose a hypothetical progression of events leading to the activation of
Similarly, the core of
One DNAse I footprint within the 5' arm of the upstream enhancer (#4A) and four others distributed over
Lack of enhancer activation may be the result of repressor activity, which may compete with activator proteins for shared DNA binding sites, inhibit or quench adjacent activators bound to a common regulatory element, or repress directly RNA Pol II transcription complex [
Genome-wide analyses of chromatin status and transcription factor binding in various tissues have revealed that 80% of the genome exert functional role [
Examining these and other data regarding
Data from cell types representing discrete steps in the myelopoietic pathway also suggest a plausible sequence of events controlling gene expression.
Studying leukemia cells representing committed myeloid progenitors with bi-potential differentiation capacity not only enables longitudinal study of the control of gene expression but to also address differences in locus activation, which may result from genetic and/or epigenetic variations such as those observed at
Current data confirm that HL-60 cells provide a model representative of human myelo-monocytic differentiation. However, in the other promyelocytic cell line NB4,
Hence M2 macrophages geared to recycle apoptotic cells and iron, fuel mitochondrial biogenesis and oxidative metabolism but limit the production of reactive oxygen species (ROS). ROS production resulting from mitochondrial respiration is controlled by modulating the expression of uncoupling proteins, e.g., UCP2 [
Understanding the regulation of
Functional validation of
Identifying all the SNPs that are located in areas of open chromatin such DNAse I hypersensitive sites which may influence
The networked UCSC and ENCODE communities and online facilities are gratefully acknowledged. The author received no specific funding for this work.