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Topical Calcineurin Inhibitors for Atopic Dermatitis: Review and Treatment Recommendations
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Atopic dermatitis (AD) is an inflammatory skin disease commonly affecting children and managed by pediatricians, primary care physicians, allergists, and dermatologists alike. For many years, the only available topical pharmacological treatment was topical corticosteroids. This changed in 2000–2001, when topical formulations of two calcineurin inhibitors (tacrolimus and pimecrolimus) were approved for short-term or chronic intermittent treatment of AD in patients ≥2 years of age, in whom other treatments have been ineffective or contraindicated. These topical calcineurin inhibitors (TCIs) quickly became a popular treatment option due at least in part to concerns over adverse events associated with prolonged topical corticosteroid use, especially in children. However, based on theoretical concerns about a possible risk of lymphoma associated with TCI use, a Boxed Warning was placed on both products in 2006. Since then, despite an extensive body of evidence, no causal relationship has been demonstrated between TCI use and an increased risk of lymphoma; however, the US FDA has concluded that a link cannot be ruled out. In fact, based on post-marketing surveillance of spontaneous, literature, and solicited reports, we report here that the lymphoma incidence in the topical pimecrolimus-exposed population is up to approximately 54-fold less than that seen in the general US population. This review summarizes the mechanism of action of TCIs, the factors that prompted the Boxed Warning, and recent TCI safety and efficacy data. Based on these data, both topical corticosteroids and TCIs should have defined roles in AD management, with TCIs favored for sensitive skin areas (e.g., face) and instances where topical corticosteroids have proven ineffective, thereby minimizing the risk of adverse effects with both drug classes.
1 Introduction
Atopic dermatitis (AD) is an inflammatory skin disease that predominantly affects children, with approximately 70 % of first diagnoses made in children <5 years of age [1]. According to a US PharMetrics study, most AD sufferers are treated by pediatricians (~30 %), dermatologists (~25 %), or primary care physicians (~20 %) [2]. Topical corticosteroids have long been and remain the mainstay of AD flare treatment; however, their use is limited by concerns about local and systemic adverse effects with extended use [3, 4]. After their approval in 2000–2001, topical calcineurin inhibitors (TCIs; tacrolimus 0.03 or 0.1 % and pimecrolimus 1 %) quickly became popular alternatives to topical corticosteroids; however, since 2006, TCI use has fallen dramatically after the addition of a Boxed Warning to each product's label about a theoretical risk of malignancy (including lymphoma). Since that time, significant new epidemiologic and clinical data have become available that challenge the validity of this warning. This article provides an update on these data, summarizes the mechanism of action of TCIs, discusses the factors that prompted the class-wide warning, and provides guidance for the optimal use of TCIs from an allergist's perspective.
2 Atopic Dermatitis: Overview
2.1 Clinical Manifestations and Prevalence
Major clinical manifestations of AD include pruritus (itching) and chronic or relapsing scaly lesions. Diagnostic criteria include evidence of itchy skin and ≥3 of the following: history of involvement of skin creases [fronts of elbows or ankles, backs of knees, or around the neck (including cheeks in children <10 years of age)], history of asthma or hay fever (or, in children <4 years of age, a history of atopic disease in a first-degree relative), history of generally dry skin in the past year, onset before the age of 2 years (in children ≥4 years of age), or visible flexural dermatitis (including the cheeks or forehead and outer aspects of limbs in children <4 years of age) [5].
Results of the International Study of Asthma and Allergies in Childhood (ISAAC) demonstrated great variability in the worldwide prevalence of AD with ranges of 0.2–24.6 % for patients 13–14 years of age (n = 663,256) and 0.9–22.5 % for patients 6–7 years of age (n = 385,853) [6]. In the US, AD is estimated to affect 10.7 % (7.9 million) of children, and the wide range in prevalence between regions (8.7–18.1 %) suggests that social and/or environmental factors may play a role in disease expression [7].
2.2 Natural History and Mechanism
3 Treatment Approaches
3.1 Emollients, Topical Corticosteroids, and the Emergence of Topical Calcineurin Inhibitors (TCIs)
There is currently no cure for AD, so disease management is focused on trigger avoidance and alleviation of symptoms. First-line maintenance therapy includes nonpharmacological treatment with various emollients and skin barrier repair agents, which have been shown to improve skin appearance and dryness and/or to reduce the need for pharmacological treatment [1, 9]. When flares occur, anti-inflammatory agents are used to control the inflammatory aspects of the disease. For many years, the main pharmacological option was topical corticosteroids; however, in December 2000, tacrolimus ointment 0.03 % (for patients ≥2 years of age) and 0.1 % (for patients >15 years of age) were approved as second-line short-term or intermittent chronic therapy for patients ≥2 years of age with moderate-to-severe AD [10]. In December 2001, pimecrolimus cream 1 % was approved for the same indication in patients ≥2 years of age with mild-to-moderate AD [11]. Due in part to concerns about corticosteroid use, TCIs quickly became a popular treatment option. Prior to the approval of tacrolimus (1997–2000), topical corticosteroids were prescribed during 34 % of all AD-related visits in the US; between 2001 and 2004, that percentage fell to 25 %, and TCIs were prescribed during 23 % of visits [12].
3.2 TCIs: Mechanism of Action
Tacrolimus and pimecrolimus are macrolactams with immunosuppressive characteristics. Both TCIs are thought to exert their immunosuppressive effects by inhibiting the activation of T lymphocytes, thereby decreasing the release of the various proinflammatory cytokines discussed previously (Fig. 1) [13]. Unlike topical corticosteroids, TCIs do not have an effect on Langerhans' cells and do not reduce the numbers of Th cells in healthy skin [13]. Transepidermal penetration of both TCIs is lower (70- to 100-fold) than that of topical corticosteroids, with the transepidermal flux of pimecrolimus in cream being approximately fivefold lower than the flux of tacrolimus in ointment [13]. Due to these characteristics, tacrolimus and pimecrolimus have been investigated for a number of other inflammatory skin diseases [14] and oral and intravenous tacrolimus is indicated for graft-versus-host prophylaxis [15].
3.3 TCIs: Safety and Efficacy Comparisons with Topical Corticosteroids
Comparative efficacy and tolerability between topical calcineurin inhibitors and topical corticosteroidsa
Tolerability results
Efficacy results
Tacrolimus vs.
Pimecrolimus vs.
Mild CS
Potent CS
Mild CS
Potent CS
Meta-analysis of studies comparing tacrolimus and pimecrolimus with each other, topical corticosteroids, or vehicle in patients with AD of any age (n = 5,301) [16]
• Both TCIs are well tolerated
Meta-analysis of randomized trials of TCIs compared with topical corticosteroids or vehicle in patients of any age with AD (n = 6,687) [17]
• Skin burning is more frequent with both TCIs than topical corticosteroids
• Neither TCI is associated with risk of skin infection compared with vehicle or topical corticosteroids
Meta-analysis of randomized controlled trials comparing tacrolimus with pimecrolimus, topical corticosteroids, or vehicle in children with AD (n = 712 tacrolimus-treated) [18]
• Tacrolimus is similar in tolerability to vehicle and pimecrolimus, but greater in tolerability than 1 % HCT
• Burning and pruritus are among the most frequent adverse events
Systematic review of randomized controlled trials of TCIs compared with topical corticosteroids or vehicle in patients of any age with AD (n = 7,378) [19]
Meta-analysis of randomized controlled trials of TCIs compared with topical corticosteroids or vehicle in children with AD (n = 4,234) [20]
• Both TCIs have tolerability profiles similar to vehicle
Meta-analysis of randomized controlled trials of tacrolimus compared with topical corticosteroids in children (n = 2,328) and adults (n = 2,849) with AD [21]
• Tacrolimus and topical corticosteroids are similar in tolerability, with the exception of skin burning
4 Boxed Warning for the TCIs
4.1 Rationale
As with many drugs, the long-term safety of TCIs had not been fully established at the time of approval, and animal studies suggested the possibility of immune system-mediated malignancy (particularly lymphomas) with systemic exposure [24]. Furthermore, oral and intravenous tacrolimus administered for systemic immune suppression in transplant recipients is associated with an increased risk of immune-mediated malignancies, including lymphomas [15]. Consequently, at approval, the FDA required long-term pediatric safety registries for both agents [25, 26].
In early 2005, the FDA's Pediatric Advisory Committee (PAC) raised concerns about the widespread use of TCIs, particularly off-label prescriptions to infants, which by January 2004 had reached approximately 525,000 (14 % of yearly prescriptions) for pimecrolimus and 69,000 (7 %) for tacrolimus [27], and heavy direct-to-consumer advertising. Based on this, the animal data (mentioned above), and malignancy reports in the FDA's adverse event reporting system (AERS; 25 malignancies, 13 lymphomas in >6.7 million potential patients), the committee recommended that a Boxed Warning be added to both products [28]. However, because the incidence of malignancy had been low in clinical studies of either TCI (>38,000 patients, including >14,000 children), they concluded that a causal link had not been established, but was possible and plausible.
On January 16, 2006, the FDA accepted the PAC's recommendations and required that the prescribing information for tacrolimus and pimecrolimus be amended with a Boxed Warning. The warning states that, although a causal relationship had not been established, "rare cases of malignancies (e.g., skin cancer, melanoma) have been reported in patients treated with topical calcineurin inhibitors [22, 23]". This ultimately resulted in a 79 % decrease in TCI prescriptions [27], loss of preferred status in many formularies, and sparked a benefit-risk debate that remains unresolved.
4.2 Criticism
The FDA's decision prompted criticism by various experts [29, 30, 31, 32] and medical associations, including the American College of Allergy Asthma and Immunology (ACAAI) and the American Academy of Allergy, Asthma, and Immunology (AAAAI) [33], and the American Academy of Dermatology (AAD) [34]. The critics asserted that the benefit-risk ratio had not been assessed appropriately, especially in light of the impact of AD on patients and the risk of significant adverse effects with topical corticosteroids [30, 31, 32]. They contended that the results of the animal studies, which were conducted with an aim of determining dosages that produced toxicity, could not be generalized to humans because of differences in administration and/or formulation, inherent biological differences between humans and animals, and large differences in systemic exposure (26- to 340-fold greater than the maximum levels observed in humans) [29, 33].
In addition, they pointed out that the incidence of lymphoma in TCI-treated patients was no greater than that seen in the general population. In fact, in the pimecrolimus post-marketing surveillance (including solicited, spontaneous, and literature reports), the incidence of any lymphoma is 0.41/100,000 patient-years of exposure [2], whereas the age-adjusted incidence of Hodgkin's and non-Hodgkin's lymphoma combined in the general population is 22.0/100,000 patient-years [35]. That is, there is up to approximately a 54-fold higher incidence of lymphoma in the general population compared with those exposed to topical pimecrolimus; however, such calculations based on post-marketing reports are subject to under-reporting. Even if only 5 % of actual lymphoma cases are reported, the adjusted incidence of lymphoma among TCI users would still be nearly threefold lower than the background incidence in the general population. Furthermore, experts agree that misdiagnosis due to overlapping presentation with cutaneous T cell lymphoma (CTCL) and an association between AD itself and cancer risk complicate the analysis [36].
5 New Evidence, Incomplete Conclusions
Epidemiological studies of topical calcineurin inhibitor use and malignancy risk (including lymphoma)a
Design and population
Survey of dermatology outpatients with AD
Nested case-controlled cohort of 3,535 patients >30 years of age
• No association between TCI use and increased risk of non-melanoma skin cancer [39]
US PharMetrics Health Claims Database
Nested case-controlled cohort of 293,253 patients of any age with AD
• No increased risk of lymphoma in TCI-treated patients compared with non-use [40]
• Severity of AD was the main factor associated with increased risk of lymphoma [40]
• 9 of 81 patients <20 years of age who developed lymphoma had TCI exposure—4 to tacrolimus, 4 to pimecrolimus, and 1 to both [38]
US PharMetrics Health Claims Database (extension of previous)
Nested case-controlled cohort of 625,915 patients of any age with AD
• No increased risk of overall lymphoma in TCI- or topical corticosteroid-treated patients compared with non-use; results were similar for patients <20 years of age [38, 44, 45]
• Possible significantly higher risk of non-Hodgkin's and T-cell lymphoma in patients treated with tacrolimus (but not pimecrolimus) compared with non-use [38, 45]
The Health Improvement Network (THIN) Electronic Medical Record Database
Nested case-control study of 3,500,194 patients <80 years of age who used TCIs or topical corticosteroids
• No association between TCI use and lymphoma riskb [41]
• Significant correlation between topical corticosteroid use and risk of lymphoma, especially skin lymphoma [41]
Kaiser Permanente California Databases
Cohort of 953,064 patients of any age with AD
• No association between TCI use and risk of malignancy [42]
• Possible association between risk of CTCL and exposure to tacrolimus (but not pimecrolimus) [42]
• 1 of 12 patients with a confirmed diagnosis of lymphoma was ≤20 years of age (this patient was exposed to both TCIs) [38]
United Health Care Health Claims Database
Propensity-matched cohort of 1,200,645 patients of any age including:
• Patients with AD who initiated pimecrolimus, tacrolimus, or medium/potent topical corticosteroids
• Patients with AD who did not initiate AD treatment
• Controls without AD who had no TCI/topical corticosteroid exposure
• No increased risk of lymphoma (including CTCL) with initiation of pimecrolimus compared with initiation of tacrolimus or medium/potent topical corticosteroids [43]
• Of patients ≤5 years of age:
○ None had a diagnosis of lymphoma during the 6-month period following the index date [38]
○ Two had a diagnosis of lymphoma overall (one patient with CTCL and one with "any lymphoma"; both were exposed to tacrolimus) [38]
Despite this large volume of epidemiological data, the FDA concluded that there still may be "a possibility of an association" between tacrolimus (pimecrolimus is not mentioned) and an increased risk of lymphoma but, "causality is difficult to determine in light of potential study biases" and "applicability of the reported results specifically to the pediatric population and the long-term safety profile of [tacrolimus] remain in question [38]".
As of May 2011, a total of 72 cases of malignancy in TCI-treated children had been reported to the FDA (17 before the Boxed Warning and 55 after): 25 lymphomas, 25 leukemias, 8 skin malignancies, and 14 other types of cancer [46]. The FDA reviewers concluded that these cases "support the previously observed potential signal for malignancies reported with TCI use"; however, they also state that the available information is not sufficient to determine causality.
6 An Allergist's Perspective: Optimizing Therapy with TCIs
6.1 Recommendations
As noted above, the total number of TCI prescriptions has fallen precipitously since 2004 [27]. This suggests that a relatively large number of patients have been denied the benefits of TCI therapy on the grounds of a speculative assessment of risk. Also implied is an increase in topical corticosteroid use, along with all its associated risks, especially when used in sensitive areas such as the face and around the eyes [12]. While care should be used in prescribing TCIs, available evidence suggests that the concerns of the PAC have not been borne out during the 7 years since the Boxed Warning was initiated. Although topical corticosteroids should remain first-line therapy for AD flares, there are a number of situations in which TCIs should be considered. Currently, TCIs are indicated for use in patients who do not respond to topical corticosteroid treatment or in whom topical corticosteroid use is contraindicated [22, 23]. In addition, for patients with particularly severe AD who require long-term treatment, chronic intermittent and proactive use of TCIs may be more appropriate than topical corticosteroids, given the limited data available for long-term use of topical corticosteroids [47]. Likewise, in sensitive skin areas such as the face, neck, or genitals, corticosteroid use may not be suitable due to a greater risk of telangiectasia and higher systemic exposure resulting from a thinner epidermal barrier in those areas [3, 4]. Furthermore, corticosteroid use in the periorbital region can lead to corticosteroid-induced vasoconstriction and glaucoma [4]. These concerns are particularly relevant in the case of children, who are more likely to have AD, more likely to have AD in sensitive-skin areas, and have a higher body surface/volume ratio that enhances the risk of systemic exposure to corticosteroids. In rare cases, systemic exposure may lead to hypothalamic–pituitary–adrenal axis suppression and growth retardation [4]. In some instances, it may also be reasonable to consider using TCIs in combination with topical corticosteroids; for example, the use of a topical corticosteroid of appropriate potency on the body (i.e., below the neck) and a TCI on the face, or in areas where topical corticosteroids have been ineffective. With such an approach, the total exposure to both TCIs and topical corticosteroids would be reduced, thereby decreasing the risk of adverse effects associated with either drug class. Furthermore, counselling patients to limit or avoid sun exposure will mitigate risk of cutaneous malignancy, as recommended in the package insert [23].
6.2 Challenges Associated with Prescribing TCIs
Due to the Boxed Warning, prescribing TCIs has become difficult due to a number of factors, not least of which is barriers to patient access and reimbursement put in place by insurers and other payers. Even when they are prescribed as indicated, the Boxed Warning often dissuades patients, and even some doctors (especially those less familiar with the history of the debate), from using them. However, it is our responsibility, as physicians, to ensure that patients receive the best possible care, particularly when first-line therapies do not provide sufficient relief, or if there are relevant safety concerns. We physicians must also sufficiently explain the benefits and risks of the therapies we prescribe, which, in the case of TCIs, may require longer consultation times. There is currently no standard method for communicating the risks and benefits of TCIs. A consensus document, directed toward patients and caregivers, that places the risks into context would be useful. Unfortunately, no such document exists. Until such a document becomes available, physicians should stay informed of the issues surrounding TCI use so that they can adequately answer questions and discuss potential problems with insurance coverage and/or preauthorization prior to prescribing. It is also important to work with pharmacists to consistently communicate the risks and benefits of pharmacotherapies for AD.
The medicines that dermatologists prescribe are safe when used as directed…The [AAD] believes that these Warnings confuse and unnecessarily worry people. Studies prove that with proper use, topical pimecrolimus and tacrolimus are not dangerous. When applied to the skin, virtually none of the medicine gets inside the body. When used properly, the medicines reduce the debilitating effect of [AD] and allow millions of people to live normal lives [48].
7 Conclusions
In the 7 years since the Boxed Warning was implemented, no conclusive proof has emerged that links TCI use to malignancy risk, despite extensive monitoring and analysis. However, a theoretical possibility remains, and so does the Boxed Warning. In this context, it may be appropriate to challenge the treatment paradigm of using TCIs only after failure of topical corticosteroids. Not adopting such a treatment strategy may deprive many patients, especially children, of effective AD management, while putting them at risk for corticosteroid-associated adverse effects. That is why the author recommends (and currently prescribes, when appropriate) TCIs for sensitive skin areas ("above the neck") and topical corticosteroids for the rest of the body ("below the neck"). In the meantime, we as physicians must remain informed about this debate and be ready to explain the benefit-risk ratios of both TCIs and topical corticosteroids to our patients and their caregivers. Continued monitoring and future studies may shed more light on this question.
Dr. Carr played a key role in the development of this manuscript. Vojislav Pejović and Michael Miller of Prescott Medical Communications Group (Chicago, IL, USA) provided medical writing and editorial support with funding support from Valeant Pharmaceuticals North America LLC (Bridgewater, NJ, USA). All content was developed independently of the funding source. Dr. Carr has received consulting fees and/or served on advisory boards for Alcon Laboratories (a division of the Novartis Group), AstraZeneca, Meda AB, Sanofi, Sunovion Pharmaceuticals Inc. (formerly Sepracor Inc.), and Teva Pharmaceutical Industries Ltd. In addition, he has been a member of speakers' bureaus for Alcon Laboratories, AstraZeneca, Meda AB, Teva Pharmaceutical Industries Ltd, and GlaxoSmithKline. He has also participated in contract research with Alcon Laboratories, Novartis Pharmaceuticals Corporation, AstraZeneca, Meda AB, Sunovion Pharmaceuticals Inc., Teva Pharmaceutical Industries Ltd, GlaxoSmithKline, ISTA Pharmaceuticals Inc. (now Bausch & Lomb), and Genentech, Inc. (a member of the Roche Group).
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Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.


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BRUSSELS, June 12 (Reuters) - The following are mergers under review by the European Commission and a brief guide to the EU merger process:
-- POSCO Chemtech, which is a subsidiary of South Korean steelmaker POSCO ; Japan's Mitsubishi Chemical Holdings Corp and Japanese trading house Mitsubishi Corp to set up a joint venture (approved June 11)
-- Private equity firm Bain Capital to acquire holding company Scandinavian Installations Refi which owns energy company Bravida with operations in Sweden, Denmark and Norway (notified June 7/deadline July 12/simplified)
-- Spanish bank Santander, Hyundai Motor Company , Hyundai Capital Services and Kia Motors UK Ltd to set up a joint venture (notified May 30/deadline July 4/simplified)
-- Finnish group Outokumpu to acquire German group ThyssenKrupp's Inoxum stainless steel unit (notified April 10/deadline extended for the second time to Oct. 24 from Sept. 26 after the companies asked for more time)
-- Belgian chemicals company Solvay and French peer Air Liquide to form a fluorine gas business joint venture )notified May 2/deadline June 12/simplified)
-- France's La Poste and Switzerland's Swiss Post to set up a joint venture for cross border mail activities (notified May 11/deadline June 20)
-- Spanish oil product company Disa Corporacion Petrolifera to acquire joint control of Shell Aviation Espana, a unit of Shell (notified April 26/deadline extended to June 21 after Spanish competition regulators asked for the case to be referred to them)
-- Dutch insurer Aegon to acquire a joint stake in Spanish life insurer Liberbank Vida from Spanish lender Liberbank (notified May 15/deadline June 22/simplified)
-- Germany's Bertelsmann to acquire a stake in German software company Bidmanagement (notified May 15/deadline June 22/simplified)
-- Swedish paper company SCA to acquire the European tissue operations of Georgia-Pacific Europe (notified May 15/deadline June 22)
-- Russia's EuroChem to acquire German potash miner K+S's nitrogen fertiliser distribution business (notified May 21/deadline June 26/simplified)
-- German engine maker Tognum and Russian engine producer TMH to form a joint venture (notified May 21/deadline June 26/simplified)
-- German car parts maker Robert Bosch to acquire the automotive service business of U.S. manufacturer SPX Service Solutions Business (notified May 21/deadline June 26)
-- U.S. technology distributor Arrow Electronics to acquire computing product distributor Altimate Group which is a unit of Irish business services group DCC Plc (notified May 21/deadline June 26)
-- Swiss-based trader Vitol and private equity investor AtlasInvest to acquire certain Swiss assets from Petroplus (notified May 21/deadline June 26/simplified)
-- Malta-based oil and aluminium company Klesch Group to acquire a subsidiary of French chemicals company Arkema (notified May 21/deadline June 26/simplfied)
-- Samsung Electronics to acquire sole control of Samsung Mobile Display Co which is now jointly controlled by Samsung Electronics and Samsung SDI Co Ltd (notified May 21/deadline June 26/simplified)
-- Hon Hai to acquire a 46.5 percent stake in Sharp Display Products which is owned by Sharp (notified May 21/deadline June 26)
-- Hong Kong's Hutchison 3G, which is part of Hutchison Whampoa, to acquire telecoms operator Orange Austria from France Telecom (notified May 7/deadline extended to June 29 from June 15 after Austrian competition regulators asked for the case to be referred to them)
-- Private equity firm CVC to acquire business consultancy Alix Partners (notified May 24/deadline June 29/simplified)
-- German animal product manufacturer Saria bio-Industries AG, which is controlled by German privately-owned water management and logistics company Rethmann, to set up a joint venture together with Danish meat processing company Danish Crown (notified May 24/deadline June 29)
-- Toshiba Tech Corp, a unit of Japan's Toshiba Corp, to buy IBM's point-of-sale terminal business (notified May 24/deadline June 29)
-- Venture capital firm BPCE to acquire joint control of staffing agency Accent Jobs For People (notified May 25/deadline July 2/simplified)
-- Swedish telecoms equipment maker Ericsson to acquire technology services company Technicolor Broadcasting Services (notified May 25/deadline July 2/simplified)
-- British telecoms operator Vodafone to acquire telecoms provider Cable & Wireless Worldwide (notified May 29/deadline July 3)
-- Geneva-based commodities trader Vitol to buy a stake in the Cockett Group which is involved in bunkering activities and is a subsidiary of South African shipping firm Grindrod (notified May 29/deadline July 3/simplified)
-- Japanese cash handling machine maker Glory Ltd to acquire Britain's Talaris Topco Ltd (notified May 30/deadline July 4)
-- Animal feed producer Forfarmers to acquire holding company Agricola which owns a group of British animal feed suppliers operating under the trade name BOCM Pauls (notified May 31/deadline July 5)
-- Germany car maker Volkswagen's Audi division to buy Italian motorcycle maker Ducati (notified May 31/deadline July 5/simplified)
-- Finnish engineering company Metso to acquire Finnish ship and power plant engine maker Wartsila's holding in their MW Power joint venture. Metso currently owns 60 percent and Wartsila 40 percent of MW Power (notified May 31/deadline July 5/simplified)
-- Private equity firm Providence Equity Partners to acquire HSE24, which operates teleshopping broadcasters in Germany (notified June 1/deadline July 6/simplified)
-- Swiss commodities trader Glencore to acquire Canadian grain handler Viterra Inc (notified June 4/deadline July 9/simplified)
-- Proposed acquisition of joint control of electronics components maker NEC TOKIN Corp. by KEMET Electronics Corp. and NEC Corp. (notified June 7/deadline July 12)
-- OK ekonomisk förening (OKEF) and Kuwait Petroleum Corporation to acquire joint control of Kuwait Petroleum (Danmark) (notified June 8/deadline July 13/simplified)
-- U.S. conglomerate United Technologies Corp to acquire U.S. aircraft components maker Goodrich (notified Feb. 20/deadline extended for the second time to Aug. 31 from Aug. 9/companies offered commitments June 11)
-- Vivendi's Universal Music Group to buy British record label EMI's recorded music unit from Citigroup Inc (notified Feb. 17/deadline extended for the second time to Sept. 6 from Aug. 8 after the Commission asked for more time)
-- Telefonica UK and Vodafone UK to set up a joint venture providing mobile commerce services (notified March 6/deadline extended for the second time to Sept. 19 from Aug. 27 after the companies requested an extension)
The European Commission has 25 working days after a deal is filed for a first-stage review. It may extend that by 10 working days to 35 working days, to consider either a company's proposed remedies or an EU member state's request to handle the case.
Most mergers win approval but occasionally the Commission opens a detailed second-stage investigation for up to 90 additional working days, which it may extend to 105 working days.
Under the simplified procedure, the Commission announces the clearance of uncontroversial first-stage mergers without giving any reason for its decision. Cases may be reclassified as non-simplified -- that is, ordinary first-stage reviews -- until they are approved. (Editing by Foo Yun Chee)


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Posted on June 10, 2009
Robinho has cast doubt over his Manchester City future by admitting any player would relish the chance to play for Barcelona.
The Brazilian left La Liga last summer, joining City from Real Madrid for a British record fee of £32.5million.
Robinho struck 14 Premier League goals during his debut campaign in England and he recently stated his commitment to City.
However, the forward has been quoted as conceding that the opportunity to play for Barca would be an attractive proposition for any player.
"So far, there has only been speculation," he told Sport. "There is nothing concrete and I haven't received any offers.
"The only thing I can say is that Barcelona are a great team and everybody would love to play for them.'
Robinho did, however, insist he remains 'comfortable' with his decision to swap Madrid for Manchester.
"I left because I was not happy. I do not regret the decision and I'm comfortable at Manchester City."


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Bodenham, Herefordshire
Historical Description
Bodenham, a village and a parish in Herefordshire. The village stands near the river Lugg, 1 mile E of Dinmore station on the Shrewsbury and Hereford Joint (L. & N.W. & G.W.) railway, and 6 ½ SSE of Leominster, under which it has a post, money order, and telegraph office ; and was once a market-town. There are remains of a large cross with a well in the village. The parish includes also the townships of Bowley, Bryan-Maund, Whitchurch-Maund, and the Moor. Acreage, 5295; population of the civil parish, 883 ; of the ecclesiastical, 878. Broadfield Court, Bodenham Manor, and Vennwood are the chief residences. The living is a vicarage in the diocese of Hereford; net value, £440 with residence. The church is a fine cruciform Early English and Decorated edifice, with a square tower. It was beautifully restored in 1891. There is a school chapel at Maund Common, and a Wesleyan chapel at the Moor.
The following is a list of the administrative units in which this place was either wholly or partly included.
|Ancient County
|Ecclesiastical parish
|Bodenham St. Michael
|Poor Law union
Any dates in this table should be used as a guide only.
Civil Registration
For general information about Civil Registration (births, marriages and deaths) see the Civil Registration page.
Directories & Gazetteers
We have transcribed the entry for Bodenham from the following:
Online maps of Bodenham are available from a number of sites:
- Bing (Current Ordnance Survey maps).
- Google Streetview.
- National Library of Scotland. (Old maps)
- old-maps.co.uk (Old Ordnance Survey maps to buy).
- Streetmap.co.uk (Current Ordnance Survey maps).
- A Vision of Britain through Time. (Old maps)
Newspapers and Periodicals
The British Newspaper Archive have fully searchable digitised copies of the following Herefordshire newspapers online:


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Declaration of Sentiments and Resolutions
Using compositional words to increase persuasiveness or effectiveness of a speech or writing.
Historians, Women's Rights Activists and questioners of Women's Right
To inform people of the changes made to the Declaration of Sentiments and Resolutions and the Women's Rights Convention.
Elizabeth Cady Stanton
Women's Rights
Signing of the Declaration of Sediments and Resolutions, Seneca Falls, July 19-20 1848
Rhetorical Appeals
ETHOS: She emphasized the injustices that women were subject to by stating the unfair powers of men.
Rhetorical Appeals
PATHOS: The strive to change women's rights.
Rhetorical Appeals
LOGOS: By giving examples as to why it was unfair.
Rhetoric Devices
Motif is a rhetorical device used in this document and the author included it to prove that women needed to be treated better.
Rhetoric Devices
Narration is a rhetorical device that is used to set up the scene and explain who is speaking and how events were resolved.
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Declaration of Sentiments and Resolutions
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Bailey Carlsonon 3 October 2013
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Black History Month & African American Timeline
Black History Month is observed every February in the United States. Learn about famous firsts by black Americans, read about the history of black history, and find information about milestones in black history.
500 Notable African American Biographies
History & Timelines
- The History of Black History
- African-American History Timeline
- Famous Firsts by African Americans
- Encyclopedia: Civil Rights
- Civil Rights Timeline
- Major Race Riots in the U.S. Timeline
- For Kids: Civil Rights Heroes
- The March on Washington
- Important Cities in Black History
- The Tuskegee Syphilis Experiment
- Timeline: Slavery in America
- Notable Speeches by African Americans
- Ten Important Supreme Court Decisions in Black History
Main Black History Month page.
- Did you know?
- For more than a billion Muslims around the world, Ramadan is a "month of blessing" marked by prayer, fasting, and charity.


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Nail Services
Going, going, gone. All the month of July 50% all Nail Enhancement, Manicures, Pedicures, and Nail Art. Open Monday - Saturday 11am - 5pm Walk In's, 9am - 11am and 5pm - 7pm by appointment only, and 12pm 6pm Sunday by appointment only! Up coming specials.... Fourth of July and Jazz Fest.
Discount on Red, White, and Blue Nail Art on natural nails free art with Full Set and Fill In's. 25% off Pedicures and free Toe Nail Art for Vet's only. Open until 4pm on the Fourth of July. The Jazz Fest on the 22scnd and the 23thrd of July 50% off all Nail Enhancement, Manicures, Pedicures, and Nail Art by appointment only. I am a licensed Nail Manicurist and I have been doing Nail sense I am knew to he Clifton area and look forward to servicing my community and beyond. My first name is customer service.
Located at Good Looks Salon 2700 Vine St ( Short Vine ) Cincinnati Ohio


text: Just wanted to let you know of a company that knows how to take care of their customers. I bought a tiny-tack last year for my Rock SOlid Plugr. Earlier this fall I broke the wire that conencts to the unit. I tried soldering it back together -- but it didn't work. When I called the company to inquire on how to repair it -- he told me he could fix it faster than tell me. I sent it to him on Monday and he fixed and returned it to me by Thursday -- even added extra wire so I could run the wires more securely. A great example of great customer service. It might be alittle thing -- but they have won a customer for life and one who will reccomend them to everyone! www.tinytach.com


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Data from: From cellular characteristics to disease diagnosis: uncovering phenotypes with supercells
Date Published: September 6, 2013
DOI: http://dx.doi.org/10.5061/dryad.v6st3
Content in the Dryad Digital Repository is offered "as is." By downloading files, you agree to the Dryad Terms of Service. To the extent possible under law, the authors have waived all copyright and related or neighboring rights to this data.
|Multicolor flow cytometry for healthy and uveitides patients
|60 times
|Multicolor flow cytometry datasets from 22 fresh peripheral blood patient samples. Please see attached ReadMe file.
|Candia_datasets.tar.gz (1.057 Gb)
|README.txt (998 bytes)
|View File Details
When using this data, please cite the original publication:
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|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|Edwin Goei <edwi...@sun.com>
|Re: documentation for the class org.apache.crimson.tree.XmlDocument
|Tue, 19 Jun 2001 21:48:50 GMT
Badie Garzaldeen wrote: > > Hello, > > I am using the class org.apache.crimson.tree.XmlDocument to make an xml > file persistent (write)and to set the DTD (setDocType), but I would have > the documentation of this class, because the setDocType-Method does not > work well. I'm not quite sure what you are asking, but using the public XmlDocument methods is discouraged because it makes your app dependent on the crimson parser. Also, those methods are there for backward compatiblity and are not really being maintained. One way to marshal/serialize a DOM is to use the jaxp.xml.transform package with an identity transform from a DOMSource to a StreamResult object. See the docs on Xalan-j for more info. -Edwin --------------------------------------------------------------------- In case of troubles, e-mail: firstname.lastname@example.com To unsubscribe, e-mail: firstname.lastname@example.com For additional commands, e-mail: email@example.com
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You can only push an innocent man so far
An ex-cop turned con threatens to jump to his death from a Manhattan hotel rooftop. The NYPD dispatch a female police psychologist to talk him down. However, unbeknownst to the police on the scene, the suicide attempt is a cover for the biggest diamond heist ever pulled.
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This post is sponsored by HYLETE. Today's post combines three of my favorite things. 1) New workout gear. 2) Working out with Tanner. 3) BURPEES! HYLETE recently offered to send a sampling of their workout apparel for both Tanner and I try out and we decided to give it the ultimate test with a sweaty [...]
partner workout
The Couple that Burpees Together…Burpee Couples Workout + HYLETE ReviewAugust 31, 2016 { 14 comments }
2016 Valentine's Day Partner Workout + My Weekly WorkoutsFebruary 14, 2016 { 1 comment }
Happy Valentine's Day! Last year I shared a Valentine's Day partner workout and I thought it would be fun to put together another one for you this year. I love this partner workout because most of the exercises are interactive and/or hands on. Sweating together is a great way for couples to connect while doing [...]
Valentine's Day Workout + Recipe InspirationFebruary 12, 2015 { 18 comments }
I'm super excited about tonight's post...we're talking Valentine's Day! I've got a really fun couple's partner workout for you and recipe inspiration. Let's talk about the workout first. I don't know about you but I love working out with a partner from time to time. It's a fun way to mix it up and motivate yourself. [...]


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October 11, 2011
Following the rejection of its last proposal, Plato Learning, a portfolio company of Thoma Bravo and HarbourVest Partners, has submitted another revised proposal to acquire Renaissance Learning (NASDAQ: RLRN). Plato has offered to pay $496 million for the provider of technology-based school improvement and student assessment programs, and this time, it has left it up to Renaissance's Board of Directors and co-founders to determine the allocation of the consideration between shareholder groups. Renaissance's Board will consider the new proposal but continues to recommend that shareholders approve the existing definitive agreement to be acquired by Permira for $455 million.
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The Age Of Spiritual Machines is a book by futurist Ray Kurzweil about the future course of humanity, particularly relating to the development of artificial intelligence and its impact on human consciousness. It is also a study on the concept of technological singularity.
The book
Originally published in 1999, the book predicts that machines with human-like intelligence will be available from affordable computing devices within a couple of decades, revolutionising most aspects of life, and that eventually humanity and its machinery will become one and the same.
In order to help the reader understand the concepts portrayed in the book (and for the book to make its predictions pseudo-realistic), the author has conversations with Molly, a typical human being. At the start of the book, Molly is a 23-year-old woman who has little understanding of the concepts that are discussed in the book, yet has an enigmatic (sometimes romantic) interest in the author, which keeps her interested. By the time the book reaches Part III, Facing the Future, Molly has somewhat of a grasp on all these concepts. It is during Part III that she physiologically and technologically evolves (as predicted by the author) as the years go by, to the point that by the year 2099 (the farthest point in the author's scope), she has shed all biological matter and has become a dynamic, conscious sub-entity within a larger, singular entity, all within a machine (a Spiritual Machine, as it were). "Molly" has become so dynamic, in fact, that she is (in her words) ready to do anything, or be anything, you want or need.
- Alex Proyas, the director of the film I, Robot, asked every cast member to read this book before filming.
- In early 2000, Mike Turner, founding member and guitarist of the Canada|Canadian band Our Lady Peace, stumbled upon the book at a bookstore, and though initially attracted by the shininess of the book, he purchased the book intrigued by the concepts that it contained. He was so inspired by the book's information that, with the rest of the band, he created the concept album Spiritual Machines. They recruited Ray Kurzweil to voice several tracks, on which he read select passages from the book.


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|Ni Kenney - I work with Ross in CapitalOne Corporate Real Estate Strateg...
Mr. Ross Patterson Jr.
Richmond, Virginia - USA
About Mr. Ross Patterson Jr.
Ross Patterson has over 18 years of experience in financial and business management. He is currently a Senior Director in the Corporate Real Estate division of Capital One Financial Corporation. In this role Ross leads a team providing business strategy, operational and portfolio analysis, planning and reporting, and financial infrastructure.
As a leader, Ross is able to draw on his diverse experience including roles in financial analysis, systems design and implementation, Activity Based costing, vendor relationship management, and operations. His experience includes roles in both large and small corporations, in multiple industries (financial services / retail / shipping). Based on both personal experience and mentoring efforts Ross is familiar with the challenges of Government contracting, and those faced by entrepreneurs.
Ross has a proven record as a motivational leader who is able to effectively build a cohesive team, communicate a vision for growth, and energize the team behind this vision. He brings an innate ability to balance powerful analytics with an awareness of the key organizational issues that shape results. He balances empowering associates with a "roll up your sleeves" attention to detail. This combination gives Ross a unique ability to frame business problems and opportunities in ways that elicit committed action.
Prior to holding the position of Senior Director in the Corporate Real Estate division of Capital One, Ross held a series of progressively senior positions in the Capital One Global Finance division, including both Corporate and business support roles, with Senior VP clients in revenue, operations, and staff units. He also held roles of increasing accountability at Circuit City Stores, including: leading a team providing financial and operational performance reporting and analysis; developing and delivering process improvements and systems optimization; negotiating program terms and managing vendor relationships. Prior to Circuit City Ross held various operations roles with an international maritime operations Government contractor.
Ross received his Bachelor of Science degree with Special Attainments in Commerce at Washington and Lee University in Lexington, VA.
Despite his challenging career Ross makes time to be involved with community organizations. He is a member of the Institute of Management Accountants (IMA). Ross also serves on several boards and committees, including the Sigma Nu Fraternity, Lamda Chapter House Corporation, the Hermitage Country Club Finance Committee, and the Board of Directors of OAR of Richmond, a non-profit organization focused on offender restoration services.
A native of Texas, Ross now lives in Richmond, Virginia with his wife, Vanessa, and their two sons. When not working, Ross likes to golf, travel and scuba dive. Ross can be reached at firstname.lastname@example.com
If you notice offensive or incorrect information, please contact us.
Karen Dickinson
Senior MIS Analyst M@
Capital One
Mr. William G. Baker Jr
Corporate Real Estat@
Capital One