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Practice Essentials
Psoriasis, which manifests most often as plaque psoriasis, is a chronic, relapsing, inflammatory skin disorder with a strong genetic basis. Plaque psoriasis (see the image below) is rarely life threatening, but it often is intractable to treatment.
See Psoriasis: Manifestations, Management Options, and Mimics, a Critical Images slideshow, to help recognize the major psoriasis subtypes and distinguish them from other skin lesions.
Signs and symptoms
Psoriatic plaques are characterized as follows:
Raised and easily palpable - Owing to the thickened epidermis, expanded dermal vascular compartment, as well as infiltrate of neutrophils and lymphocytes
Irregular to oval in shape
One to several centimeters in size
Well defined, with sharply demarcated boundaries
Very distinctive rich, full red color; lesions on the legs sometimes carry a blue or violaceous tint
Typically have a dry, thin, silvery-white or micaceous scale
Typically have a high degree of uniformity, with few morphologic differences between the 2 sides
Range in number from a few to many at any given time
Most often located on the scalp, trunk, and limbs, with a predilection for extensor surfaces, such as the elbows and knees
Symmetrically distributed over the body
May, in the case of smaller plaques, coalesce into larger lesions, especially on the legs and sacral regions
Other manifestations of plaque psoriasis include the following:
Pruritus - One of the main symptoms of plaque psoriasis
Nail psoriasis - Nails may exhibit pitting, onycholysis, subungual hyperkeratosis, or the oil-drop sign
Inverse psoriasis - A variant of psoriasis that spares the typical extensor surfaces and affects intertriginous areas (ie, axillae, inguinal folds, inframammary creases) with minimal scale
Psoriatic arthritis - Occurs in approximately 10-20% of all cases of plaque psoriasis
Manifestations of the psoriatic arthritis include the following:
Red, warm, tender, and inflamed joints
Joint deformity
Sausage digits
In children with plaque psoriasis, plaques are not as thick, and the lesions are less scaly. Psoriasis often appears in the diaper region in infancy and in flexural areas in children. The disease more commonly affects the face in children than it does in adults.
Laboratory studies
The diagnosis of psoriasis is almost always made on the basis of clinical findings. Laboratory investigations are rarely indicated.
Skin biopsy
Skin biopsy can confirm the diagnosis of plaque psoriasis. This procedure, however, is usually reserved for the evaluation of atypical cases or for excluding other conditions in cases of diagnostic uncertainty.
Histologic epidermal findings include the following:
Mitotic activity of basal keratinocytes is increased almost 50-fold, with keratinocytes migrating from the basal to the cornified layers in only 3-5 days rather than the normal 28-30 days
The epidermis becomes thickened or acanthotic in appearance, and the rete ridges increase in size
Abnormal keratinocyte differentiation is noted throughout the psoriatic plaques, as manifested by the loss of the granular layer
Alternating collections of neutrophils are sandwiched between layers of parakeratotic stratum corneum, which is virtually pathognomonic for psoriasis
Histologic dermal findings include the following:
Signs of inflammation can be observed throughout the dermis
Marked hypervascularity and an increase in the size of the dermal papillae occur
An activated CD3 + lymphocytic infiltrate is noted around blood vessels
An aggregation of neutrophils in the dermis occurs that extends up into the epidermis
Topical therapy
Topical agents used (often concurrently) to treat plaque psoriasis include the following:
Coal tar
The 2 main forms of phototherapy are as follows:
Ultraviolet B (UVB) irradiation - UVB therapy is usually combined with one or more topical treatments
Psoralen plus ultraviolet A irradiation (PUVA) - This treatment uses the photosensitizing drug methoxsalen (8-methoxypsoralen) in combination with UVA irradiation to treat patients with more extensive disease
Systemic therapy
Systemic treatment is initiated only after topical treatments and phototherapy have proved unsuccessful. Systemic therapy should also be considered for patients with very active psoriatic arthritis, as well as for patients whose disease is physically, psychologically, socially, or economically disabling. [1, 2, 3, 4]
Biologic therapy
Biologic therapies provide selective, systemic, immunologically directed interventions, including the following, at key steps in the pathogenesis of plaque psoriasis [5] :
Inhibition of the initial cytokine release and Langerhans cell migration
Targeting of activated T cells, prevention of further T-cell activation, and elimination of pathologic T cells
Blockage of interactions that lead to T-cell activation or migration into tissue
Alteration of the balance of T-cell types
Psoriasis is a common, chronic, relapsing, inflammatory skin disorder with a strong genetic basis. The plaque type of psoriasis is the most common, although several other distinctive clinical variants of psoriasis are recognized (eg, Guttate Psoriasis; Psoriasis, Nails; Psoriasis, Pustular; Psoriatric Arthritis).
Plaque psoriasis is most typically characterized by circular-to-oval red plaques distributed over extensor body surfaces and the scalp. The plaques usually exhibit scaling as a result of epidermal hyperproliferation and dermal inflammation. The extent and duration of plaque psoriasis is highly variable from patient to patient. Acute flares or relapses of plaque psoriasis may also evolve into more severe disease, such as pustular or erythrodermic psoriasis.
Up to 10-20% of patients with plaque psoriasis also experience psoriatic arthritis. A population-based study by Wilson et al that spanned more than 30 years reported that less than 10% of psoriasis patients develop clinically recognized psoriatic arthritis. The clinical features that were associated with an increased chance of leading to psoriatic arthritis were reported as being scalp lesions, nail dystrophy, and intergluteal or perianal psoriasis. [10]
For more information, see Psoriasis.
The pathophysiology of psoriasis must be understood in terms of the prominent pathologies occurring in both major components of the skin—the epidermis and the dermis.
Psoriasis is fundamentally an inflammatory skin condition with reactive abnormal epidermal differentiation and hyperproliferation. Current research suggests that the inflammatory mechanisms are immune based and most likely initiated and maintained primarily by T cells in the dermis. [11]
In this model, antigen-presenting cells in the skin, such as Langerhans cells, are believed to migrate from the skin to regional lymph nodes, where they interact with T cells. Presentation of an as yet unidentified antigen to the T cells, as well as a number of co-stimulatory signals, triggers an immune response, leading to T-cell activation and the release of cytokines.
Co-stimulatory signals are initiated via the interaction of adhesion molecules on the antigen-presenting cells, such as lymphocyte function–associated antigen (LFA)–3 and intercellular adhesion molecule-1, with their respective receptors CD2 and LFA-1 on T cells. These T cells are released into the circulation and traffic back into the skin.
Reactivation of T cells in the dermis and epidermis and the local effects of cytokines such as tumor necrosis factor lead to the inflammation, cell-mediated immune responses, and epidermal hyperproliferation observed in persons with psoriasis.
An interleukin (IL)-12–related cytokine, IL-23, is involved in the establishment of chronic inflammation and in the development of a T helper (Th)–cell subset producing IL-17. These cells, which are designated Th17, are distinct from Th1 and Th2 populations. Th17 cells are now recognized as a third T-effector cell subset, and the IL-23/IL-17 pathway has been implicated in the induction and progression of a number of inflammatory diseases, including psoriasis. [12]
Environmental factors
Infection and a number of physical agents (eg, HIV infection, alcoholism, smoking, UV light) all can affect the course, duration, and clinical appearance of plaque psoriasis. See Etiology of Plaque Psoriasis, below, for more details on the role of environmental factors.
Genetic factors
HLA-B13, -B17, and -Cw6 are all associated with plaque psoriasis. Multifactorial inheritance mechanisms and etiologies without any genetic component have not yet been excluded, although many families appear to exhibit autosomal dominant patterns of inheritance with decreased penetrance. Studies of twin siblings have shown concordant disease in 73% of monozygotic twins compared with 20% in dizygotic twins.
Several putative genetic susceptibility loci have also been identified, including psoriasis susceptibility 1 (PSOR1) on chromosome 6, which is associated with up to 50% of cases. Six other psoriasis susceptibility loci (PSOR2, PSOR3, PSOR4, PSOR5, PSOR6, PSOR7) have been discovered, as well as the transcription factor RUNX1. While this certainly points to genetic mechanisms, the absence of 100% concordance among monozygotes suggests that environmental factors must play a role in the pathophysiology of this disease.
All types of trauma have been associated with the development of plaque psoriasis (eg, physical, chemical, electrical, surgical, infective, and inflammatory injury). Even excessive scratching can aggravate or precipitate localized psoriasis. The development of psoriatic plaques at a site of injury is known as the Koebner reaction.
Most patients consider sunlight to be beneficial for their psoriasis; they report a decrease in illness severity during the summer months or periods of increased sun exposure. However, a small minority of patients find that their symptoms are aggravated by strong sunlight, and these individuals actually experience a worsening of their disease in the summer. A severe sunburn can lead to an exacerbation of plaque psoriasis via the Koebner reaction.
Pharyngeal streptococcal infections have been shown to produce a clinically distinctive disease flare known as guttate psoriasis. Some evidence suggests that subclinical streptococcal colonization or overgrowth could be responsible for refractory plaque psoriasis.
HIV infection
An increase in psoriasis activity has been observed in patients who are infected, or become infected, with HIV. The extent and severity of skin disease initially appears to parallel the disease stage. Psoriasis often becomes less active in advanced HIV infection.
A number of medications have been shown to cause an exacerbation of psoriasis. Lithium and withdrawal from systemic corticosteroids are well known to cause flares of disease. Beta-blockers, antimalarials, and nonsteroidal anti-inflammatory drugs (NSAIDs) have also been implicated.
Psychogenic/emotional factors
Many patients report an increase in psoriasis severity with psychological stress. A clear cause-and-effect relationship between disease exacerbation and stress unfortunately has not been proven. Patients may show a decreased capacity to cope with their treatment regimen with higher levels of stress. Pruritus in the setting of increased anxiety or depression may promote scratching and a Koebner reaction.
An increased risk of chronic plaque psoriasis exists in persons who smoke cigarettes.
Alcohol consumption
Alcohol consumption is considered a risk factor for psoriasis, particularly in young to middle-aged men.
Endocrinologic factors
Psoriasis severity has been noted to fluctuate with hormonal changes. Disease incidence peaks at puberty and during menopause. During pregnancy, symptoms are more likely to improve than worsen, if any changes occur at all. In contrast, the disease is more likely to flare in the postpartum period, again if any changes occur at all.
Plaque psoriasis occurs worldwide, although its prevalence varies with race, geography, and environmental factors (eg, sun exposure). In the United States, 1-2% of the population has plaque psoriasis.
Family history has been shown to predict disease occurrence. When both parents are affected by psoriasis, the rate in siblings of probands is as high as 50%. When one parent is affected, the rate is 16.4%. When neither parent has psoriasis, only 7.8% of siblings of probands are affected.
Of patients with psoriasis, 36-71% have one relative who is also affected by psoriasis. For siblings of patients whose psoriasis appeared before age 15 years, a 3-fold higher risk exists of developing disease compared with siblings of patients who first presented after age 30 years.
Psoriasis affects adult males and females equally. Among children and adolescents, plaque psoriasis has been found to affect females more than males, but this observation may be due to the earlier age of onset in females.
Plaque psoriasis first appears during 2 peak age ranges. The first peak occurs in persons aged 16-22 years, and the second occurs in persons aged 57-60 years. Females develop plaque psoriasis earlier than males, and patients with a positive family history for psoriasis also tend to have an earlier age of onset.
Mortality and morbidity
Disease-related mortality is exceedingly rare in psoriasis. Even then, mortality is related primarily to therapy: systemic corticosteroid therapy may provoke pustular flares of disease, which can be fatal; methotrexate therapy may result in hepatic fibrosis; and phototherapy (eg, psoralen plus UVA [PUVA]) may induce skin cancers, with subsequent metastasis.
Morbidity is a much greater problem in patients with psoriasis; it includes pruritus, dry and peeling skin, fissuring, self-consciousness and embarrassment about appearance, inconvenience, and the adverse effects and high cost of antipsoriatic treatment regimens. By far, reduced quality of life is the most significant morbidity. Studies have demonstrated that patients with psoriasis have deficiencies in quality of life similar to those for persons with congestive heart failure.
An association between psoriasis, obesity, and cardiovascular comorbidity was been recognized amongst patients with plaque psoriasis. This appears to be strongest in younger patients with severe disease. The association seems to be related to the metabolic syndrome, a state of chronic systemic inflammation characterized by at least 3 of the following:
Abdominal obesity
Impaired glucose regulation
Reduced high-density lipoprotein levels
Psoriasis and obesity are now believed to share similar mediators (eg, cytokines tumor necrosis factor [TNF]–alpha and IL-6) that drive the inflammatory process in these conditions. This finding, as it becomes further elucidated, may have future implications on health screening and treatment of patients with psoriasis. [13]
Racial disparity in psoriasis
Psoriasis can affect persons of any race; however, epidemiologic studies have shown a higher prevalence in western European and Scandinavian populations. In these groups, 1.5-3% of the population is affected by the disease.
The highest documented disease prevalence is in Arctic Kasach'ye, with 12% of the population affected, followed by Norway, where 4.8% of the population has psoriasis. Lower prevalence rates for psoriasis have been reported among Japanese and Inuit populations.
Psoriasis is thought to be rare in West Africans and African Americans and is nearly absent in North American Indians. Psoriasis was undetected in the Samoan population and in a study that examined 26,000 South American Indians.
Clinical Presentation
Patient history
The typical history given by a patient with plaque psoriasis is relatively straightforward: patients report prominent itchy, red areas with increased skin scaling and peeling. Patients are particularly aware of lesions on the scalp and extensor surfaces. Patients typically are self-conscious about their lesions and commonly report using clothing to cover affected sites and avoiding potentially embarrassing social activities.
Patients commonly recognize that new lesions appear at sites of injury or trauma to the skin. This isomorphic phenomenon (Koebner reaction) typically occurs 7-14 days after the skin has been injured and has been found in 38-76% of patients with plaque psoriasis. In some patients, so-called reverse-Koebner reactions have also been noted in which preexisting psoriatic plaques actually clear after injury or trauma to the skin.
Patients may report that their disease worsens in the winter and improves in the summer.
Significant joint pain, stiffness, and deformity are reported in the 10-20% of patients with psoriasis who develop psoriatic arthritis.
Physical examination
Several cardinal features of plaque psoriasis can be readily observed during the physical examination.
Psoriasis manifests as elevated lesions that vary in size from one to several centimeters (see image below). The thickened epidermis, expanded dermal vascular compartment, and infiltrate of neutrophils and lymphocytes account for the psoriatic lesions being raised and easily palpable. The number of lesions may range from few to many at any given time.
The plaques are irregular to oval and are most often located on the scalp, trunk, and limbs, with a predilection for extensor surfaces such as the elbows and knees. Smaller plaques may coalesce into larger lesions, especially on the legs and sacral regions (see image below). Fissuring within plaques can occur when lesions are present over joint lines or on the palms and soles.
Well-circumscribed margins
Psoriatic plaques are well defined and have sharply demarcated boundaries. Psoriatic plaques occasionally appear to be immediately encircled by a paler peripheral zone referred to as the halo or ring of Woronoff.
Red color
The color of psoriatic lesions is a very distinctive rich, full, red color. Lesions on the legs sometimes carry a blue or violaceous tint.
Psoriatic plaques typically have a dry, thin, silvery-white or micaceous scale; however, the amount and thickness of this scale is quite variable. Removing the scale reveals a smooth, red, glossy membrane with tiny punctate bleeding points. These points represent bleeding from enlarged dermal capillaries after removal of the overlying suprapapillary epithelium. This phenomenon is known as the Auspitz sign.
Psoriatic plaques tend to be symmetrically distributed over the body. Lesions typically have a high degree of uniformity with few morphologic differences between the 2 sides.
Pruritus, one of the main symptoms of plaque psoriasis, is quite variable in intensity but should not be ignored. Emotional instability (eg, high levels of anxiety, depression) that might be induced by the disease often manifests as an increased tendency to scratch.
Nail psoriasis
Nail changes are commonly observed in patients with plaque psoriasis. Nails may exhibit pitting, onycholysis, subungual hyperkeratosis, or the oil-drop sign. A proper assessment of any patient suspected of having psoriasis should include careful examination of the nails.
Psoriasis in children
Plaque psoriasis manifests slightly differently in children. Plaques are not as thick, and the lesions are less scaly. Psoriasis may often appear in the diaper region in infancy and in flexural areas in children. The disease more commonly affects the face in children compared with adults.
Inverse psoriasis
This is a variant of psoriasis that spares the typical extensor surfaces and affects intertriginous (ie, axillae, inguinal folds, inframammary creases) areas with minimal scale.
Psoriatic arthritis
Approximately 10-20% of all cases of plaque psoriasis are associated with psoriatic arthritis. Signs of psoriatic arthritis include the following:
Red, warm, tender, and inflamed joints
Joint deformity
Sausage digits
Patients with obesity and psoriasis may have an increased risk of cardiovascular disease. This association appears to be strongest in younger patients with severe disease and may be related to the metabolic syndrome. [13]
Alcoholism can be considered a complication of psoriasis. Male patients with severe disease are particularly at risk for this type of substance abuse.
Differential Diagnosis
The differential diagnosis of plaque psoriasis includes the following:
Laboratory Studies
The diagnosis of psoriasis is almost always made on the basis of clinical findings. Laboratory investigations are rarely indicated. In severe cases, patients may have mild hyperuricemia and low folate levels, presumably because of enhanced epidermopoiesis.
Skin Biopsy
Skin biopsies can confirm the diagnosis of plaque psoriasis; however, this is usually reserved for the evaluation of atypical cases or for excluding other conditions in cases of diagnostic uncertainty. See Histologic Findings, below, for more details on plaque histology.
Histologic Findings of the Epidermis
Mitotic activity of basal keratinocytes is increased almost 50-fold, with keratinocytes migrating from the basal to the cornified layers in only 3-5 days rather than the normal 28-30 days. With hyperproliferation of skin cells, the epidermis becomes thickened or acanthotic in appearance and the rete ridges increase in size.
Abnormal keratinocyte differentiation is noted throughout the psoriatic plaques, as manifested by the loss of the granular layer. The stratum corneum is also thickened, and the retention of cell nuclei in this layer is referred to as parakeratosis.
Neutrophils and lymphocytes can be observed migrating upwards from the dermis into the acanthotic epidermis. Neutrophils may form localized collections known as Munro microabscesses. The presence of alternating collections of neutrophils sandwiched between layers of parakeratotic stratum corneum is virtually pathognomonic for psoriasis. (See image below.)
Histologic Findings of the Dermis
Signs of inflammation can be observed throughout the dermis in persons with plaque psoriasis. Marked hypervascularity and an increase in the size of the dermal papillae occur. An activated CD3+ lymphocytic infiltrate is noted around blood vessels, with T cells expressing cutaneous lymphocyte–associated antigen, co-stimulatory molecules such as CD2, and lymphocyte function-associated antigen–1 (LFA-1) adhesion molecules. An aggregation of neutrophils in the dermis occurs that extends up into the epidermis.
Overview of Treatment
Plaque psoriasis is a chronic skin condition. Any approach to the treatment of this disease must be considered for the long term. Treatment regimens must be individualized according to age, sex, occupation, personal motivation, other health conditions, and available resources.
Disease severity is defined not only by the number and extent of plaques present but also by the patient's perception and acceptance of the disease. Treatment, therefore, must be designed with the patient's specific expectations in mind rather than the extent of the body surface area involved. [14]
Many treatments exist for psoriasis; however, the construction of an effective therapeutic regimen is not necessarily complicated. Three basic treatment modalities are available for the overall management of psoriasis: topical agents; phototherapy; and systemic agents, including biologic therapies. All of these treatments may be used alone or in combination.
American Academy of Dermatology Guidelines
The American Academy of Dermatology has published guidelines of care for the management of psoriasis and psoriatic arthritis. See the following sections:
Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics [15] (published 2008, sunset 2013; update in progress)
Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics [16] (published 2008, sunset 2013; update in progress)
Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies [17] (published 2009, sunset 2014)
Section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents [18] (published 2009, sunset 2014)
Section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy [19] (published 2010, sunset 2015)
Topical Therapy
Outpatient topical therapy is the first-line treatment of plaque psoriasis. A number of topical treatments are available (eg, corticosteroids, coal tar, anthralin, calcipotriene, tazarotene). [21]
No single topical agent is ideal for plaque psoriasis, and many are often used concurrently in a combined approach. With the different adverse effect profiles for the various agents, using a rotational therapeutic approach in which different topical agents are used sequentially over time in the same patient is common.
In general, the effects of topical therapy should become evident within the first 2-3 weeks of use. Clearing of scale is usually observed first, followed by flattening of the treated plaques. Resolution of erythema may take 6-8 weeks.
Auxiliary agents such as keratolytics can often be added to these preparations. However, some auxiliary agents are incompatible with the active ingredients of these preparations. For example, salicylic acid inactivates calcipotriene. On the other hand, agents such as anthralin require the auxiliary agent salicylic acid for chemical stability.
Initiate phototherapy only in the presence of extensive and widespread disease (generally practically defined as more lesions than can be easily counted). Resistance to topical treatment is another indication for phototherapy.
The 2 main forms of phototherapy are ultraviolet B (UVB) irradiation and psoralen plus ultraviolet A irradiation (PUVA). Proper facilities are required for both UVB irradiation and PUVA photochemotherapy.
UVB irradiation uses light with wavelengths of 290-320 nm (in comparison, the visible light range is 400-700 nm). Narrow-band UVB phototherapy uses a fluorescent bulb with a narrow emission spectrum that peaks at 311 nm. This selective and relatively longer wavelength is more effective than broadband UVB for the treatment of plaque-type psoriasis, and poses less risk of burning. [22] Excimer laser UVB therapy can deliver high-dose light to limited plaques.
UVB therapy is usually combined with one or more topical treatments. The Goeckerman regimen uses coal tar followed by UVB exposure and has been shown to induce disease remission in more than 80% of patients. The Ingram method comprises anthralin application following a tar bath and UVB treatment. At present, UVB is more commonly combined with topical corticosteroids, calcipotriene, tazarotene, or simply bland emollients. Etanercept and narrow-band UVB combination therapy reportedly was successful. [23]
UVB phototherapy is extremely effective for treating moderate-to-severe plaque psoriasis. The major drawback of this therapy is the time commitment required for treatments and the accessibility of the UVB equipment. Patients may dislike the unpleasant odor when coal tar is added.
Home ultraviolet therapy can overcome some of the logistical problems associated with phototherapy. Because of the expense of the home units, it is most suitable for patients who require long-term maintenance therapy.
PUVA photochemotherapy, also known as PUVA, uses the photosensitizing drug methoxsalen (8-methoxypsoralen) in combination with UVA irradiation to treat patients with more extensive disease. UVA irradiation uses light with wavelengths of 320-400 nm. PUVA interferes with DNA synthesis, decreases cellular proliferation, and induces apoptosis of cutaneous lymphocytes, leading to a localized immunosuppression.
More than 85% of patients report relief of disease symptoms with 20-30 treatments. Therapy is usually administered 2-3 times per week in an outpatient setting, with maintenance treatments every 2-4 weeks until remission.
Adverse effects of PUVA therapy include nausea, pruritus, and a burning sensation. Long-term complications include increased risks of photo damage to the skin and (more importantly) skin cancer. PUVA has been combined with oral retinoid derivatives to decrease the cumulative dose of UVA radiation to the skin.
Systemic Agents
Initiate systemic treatment only after both topical treatments and phototherapy have proved unsuccessful. Consider systemic therapy for patients with very active psoriatic arthritis. Patients who have disease that is physically, psychologically, socially, or economically disabling are also considered candidates for systemic treatment. All patients must be informed of the risks and adverse effects of systemic therapy before treatment is initiated. [2, 3, 4]
Plaque psoriasis appears to respond better to combination topical/systemic therapy than to systemic treatment alone. In a randomized study, adding a topical corticosteroid to etanercept therapy in patients with moderate to severe plaque psoriasis proved to be a more effective treatment than etanercept alone. [24] In the study, which involved 592 adult patients with a Psoriasis Area and Severity Index (PASI) score of 10 or higher and with 10% or more of their body surface area affected by psoriasis, treatment consisted of either etanercept alone or etanercept plus topical clobetasol propionate foam. Significant differences favoring combination therapy were seen at week 12, including percentage of improvement in the PASI score (76.5% for combination therapy vs 68.2% for etanercept alone). [24]
Two clinical studies, ESTEEM 1 and ESTEEM 2, showed that patients treated with apremilast experienced significant, clinically meaningful improvement in plaque psoriasis at week 16 as measured by the PASI score. Apremilast was approved by the FDA for the treatment of plaque psoriasis in September 2014. [1]
Biologic Therapies
These relatively new systemic therapies provide selective, immunologically directed intervention at key steps in the pathogenesis of the disease. [5] These steps include the following:
Inhibiting the initial cytokine release and Langerhans cell migration
Targeting activated T cells, preventing further T-cell activation, and eliminating pathologic T cells
Blocking the interactions that lead to T-cell activation or migration into tissue
Altering the balance of T-cell types
As with the systemic agents, biologic therapies are typically reserved for more severe and recalcitrant cases. [26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37] Patients with active psoriatic arthritis in addition to their skin disease should also be considered.
In a study completed by the Psoriatic Arthritis Study Group, beneficial effects were observed for patients with psoriasis and psoriatic arthritis on stable doses of methotrexate when one or more courses of intramuscular alefacept were added. Further benefit in psoriatic arthritis was apparent after a second course of alefacept, and no additional toxicity was observed. [38]
Psoriasis of the palms and soles is more difficult to treat than psoriasis on other body sites. Adalimumab is effective, but only 31% of patients treated with adalimumab for hand or foot psoriasis in a placebo-controlled trial achieved clear or almost clear. [39]
In 2017, the US Food and Drug Administration (FDA) approved the addition of moderate-to-severe fingernail psoriasis data to the adalimumab prescribing information, based on results from a phase 3, multicenter, randomized, double-blind, parallel-arm, placebo-controlled clinical trial. [40]
Guselkumab (Tremfya) was approved by the FDA in July 2017 for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. It is a human monoclonal IgG1-lambda antibody that selectively binds to the p19 subunit of interleukin (IL)–23. IL-23 is a natural cytokine associated with inflammatory and immune responses. Guselkumab inhibits the proinflammatory actions of IL-23, thereby decreasing cytokine and chemokine release.
Guselkumab's approval was based on three phase 3 studies that included more than 2000 patients.
In the VOYAGE 1 trial, guselkumab was compared with adalimumab. At 16 weeks, at least 7 of 10 patients treated with guselkumab achieved at least 90% clearer skin (Psoriasis Area and Severity Index [PASI 90]) and more than 80% demonstrated cleared or almost cleared skin. Patients who achieved PASI 90 at week 28 maintained that response at week 48. [41] Similar results were shown in the VOYAGE 2 trial that included adalimumab nonresponders. [42]
Guselkumab also demonstrated effectiveness in patients who had an inadequate response to ustekinumab. [43]
The first IL-17A inhibitor, secukinumab (Cosyntex), was approved by the FDA in January 2015. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses and plays a key role in the pathogenesis of plaque psoriasis. Approval was based on the efficacy and safety outcomes that included more than 3990 patients.
In two pivotal trials, secukinumab was shown to be superior compared with placebo at week 12 with respect to the proportion of patients who had a reduction of greater than 75% from baseline in the PASI score (PASI 75). The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept. In the ERASURE study (Efficacy of Response And Safety of two fixed secUkinumab REgimens in psoriasis), the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo. In the FIXTURE study (Full year Investigative eXamination of secukinumab vs. eTanercept Using 2 dosing Regimens to determine Efficacy in psoriasis), the rates were 77.1% with 300 mg of secukinumab, 67% with 150 mg of secukinumab, 44% with etanercept, and 4.9% with placebo (P <.001 for each secukinumab dose vs comparators). [25]
A second IL-17A inhibitor, ixekizumab (Taltz), was approved in March 2016. Efficacy was observed in two prospective, double-blind, multicenter, phase 3 trials (UNCOVER 2, UNCOVER 3) that compared ixekizumab to placebo and etanercept. Ixekizumab (q2wk or q4wk) showed greater efficacy (measured by PASI 75) compared with placebo or etanercept (P <.0001). Greater proportions of patients given ixekizumab achieved PASI 90 by week 2 compared with etanercept in both studies (UNCOVER 2: P=.0002 [ixekizumab q4wk] and P <.0001 [ixekizumab q2wk]; UNCOVER 3: P <.0001 [ixekizumab q4wk] and P=.0001 [ixekizumab q2wk]). [8] IL-17 inhibitors may be associated with a small increase in the incidence of Candida infections. [44]
Brodalumab (Siliq), another monoclonal antibody that targets IL-17, was approved in February 2017. Approval was contingent upon including a boxed warning in the prescribing information warning of the risk of suicide and suicidal ideation, particularly in patients with a history of suicidality or depression. Because of the observed suicidal behavior, brodalumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).
Approval of brodalumab was based on data from the AMAGINE phase III pivotal studies. At the 210-mg dose, brodalumab was shown to be effective in total skin clearance of psoriasis compared with placebo and superior to ustekinumab at week 12 in two replicate comparator trials involving over 3500 patients. [9]
Consider consultation with a rheumatologist for patients who have evidence of psoriatic arthritis. Patients with cardiovascular comorbidities should be considered for referral to a cardiologist. Evidence-based guidelines have been published on the management of cardiovascular morbidities. [45]
Alcohol is considered a risk factor for psoriasis in young to middle-aged males. All patients with psoriasis should avoid or minimize alcohol use; patients with dependency states should be appropriately treated. Otherwise, specific dietary restrictions or supplements other than a well-balanced and adequate diet are unimportant in the management of plaque psoriasis.
Avoiding specific exacerbating factors (see Etiology of Plaque Psoriasis for details) may help prevent or minimize flare-ups of psoriasis in some patients, although the cause of disease exacerbation in many patients often is unknown.
Complications of Treatment
Overly aggressive use of topical steroids could produce progression from plaque psoriasis to generalized pustular or erythrodermic forms. Topical steroids used with occlusion increase the risk of developing cutaneous atrophy. Potential adverse effects of systemic agents and phototherapy should be monitored on a regular basis and treated as soon as possible.
Patient Education
Patient education is one of the foundations for managing this chronic and typically relapsing disorder. Not only is psoriasis associated with morbidity, its treatment can also cause significant adverse effects (even death in rare instances). Patients should be familiar with these details in order to make proper and informed decisions about therapy.
The National Psoriasis Foundation is an excellent organization that provides support to patients with psoriasis.
For patient education information, see the Psoriasis Center, as well as What Is Psoriasis?, Plaque Psoriasis, Types of Psoriasis, Understanding Psoriasis Medications, and Nail Psoriasis.
Prognosis of Plaque Psoriasis
The course of plaque psoriasis is unpredictable. Predicting the duration of active disease, the time or the frequency of relapses, or the duration of a remission is impossible. The disease rarely is life threatening but often is intractable to treatment, with relapses occurring in most patients.
Both early onset and a family history of disease are considered poor prognostic indicators. Some suggest that stress is also associated with an unfavorable prognosis.
Environmental factors (particularly sunlight and warm weather) help alleviate the disease and are considered advantageous. Methotrexate, PUVA, cyclosporine, oral retinoids, and biologic therapies all have helped induce and maintain remission in severe cases of plaque psoriasis.
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- Practice Essentials
- Overview
- Pathophysiology
- Etiology
- Epidemiology
- Presentation
- Differential Diagnosis
- Laboratory Studies
- Skin Biopsy
- Histologic Findings of the Epidermis
- Histologic Findings of the Dermis
- Overview of Treatment
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A four-bedroom house owned by a designer who's been lauded in "Better Homes & Gardens" magazine is on the market at $2.8 million.
The house, built in 2013, sits on a quarter-acre corner lot in the Baycrest neighborhood. The 2,900-square foot residence was featured on the Newport Harbor High School Home and Garden Tour in 2014.
The residence is owned by interior designer Raili Clasen and her husband Ryan. Raili Clasen's projects have appeared in various magazines, including "C Home," "HGTV Magazine" and "Cottage Style."
"Better Homes and Gardens" named her a 2013 "Stylemaker of the year."
Clasen described her eclectic style as "kitchy and cool" in the story, "Designers to watch" published in the Register's OC Home magazine in 2014.
"HGTV Magazine" characterized the property the Clasens bought in 2013 as a "bland 1959 ranch house," but said they could see beyond the cramped spaces:
"When they moved in eight months later … the place was unrecognizable."
The piece said the couple's son liked to skateboard through the new, open-floor-plan rooms; Raili Clasen called the vibe a "high-end camp."
Interiors include a soaring, great room ceiling, wide plank white oak floors and a variety of finishes in stone, marble, wood and tile for a mix of rustic and industrial looks.
The listing by Chris Brigandi of Arbor Real Estate Professionals puts it this way: "Scandinavian design melds with modern farmhouse and meets the California coast."
A swimming pool and spa, fire pit, outdoor dining and lounging decks, built-in barbecue and a bocce ball court fill out the grounds.

subset: commoncrawl


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Quick Description
Located 1.1 km from Tennis Stadium, Luxury Flat in DownTown offers pet-friendly accommodations in Rabat. Luxury Flat in DownTown features views of the city and is 1.4 km from Polish Embassy. Free WiFi is featured throughout the property and private parking is available on site.
There is a sitting area and a kitchen equipped with a dishwasher. A flat-screen TVwith cable channels, as well as a laptop and a computer are provided. Other facilities at Luxury Flat in DownTown include a spa center.
Free use of bicycles is available at the property and the area is popular for horseback riding. French Embassy is 1.4 km from Luxury Flat in DownTown, and Stadium is 1.9 km from the property. Guests can enjoy various activities in the area, including windsurfing and biking. The nearest airport is Sale Airport, 9.7 km from Luxury Flat in DownTown.
L'Ocean is a great choice for travelers interested in sightseeing, city walks and beaches.


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The Opioid Crisis: Which Treatments Work for those Suffering with Addiction? (HealthNewsDigest.com) - Great Neck, NY, September 15, 2016 - As opioid addiction cuts a broad swath of death and destruction across every regional and demographic group in the United States, millions of addicts and their families grasp desperately for help.
"The addict's struggle to recover is one of the tragedies of the addiction crisis," says neurologist and addiction medicine specialist Dr. Russell Surasky with Surasky Neurological Center for Addiction. "Even those most motivated to shake addiction often fall into what seems to be an unending cycle of drug use, detoxification, temporary sobriety, and relapse. Caught in the grip of repeated withdrawal and relapse, many turn to the hope offered by 'medication-assisted treatment', which can ease the symptoms of withdrawal and reduce cravings."
But the most frequently used medications - methadone and Suboxone® - offer only a short-term fix at best and fail to address the underlying issues that drive users back to drugs. A third medication, Vivitrol®, has a different chemical profile and is more likely to support a permanent recovery. Why is opioid addiction so difficult to overcome?
"Addiction is a complex disease," says Dr. Surasky. "It is caused by a combination of biological, behavioral, and environmental factors, all of which have to be addressed to effect a cure. Understanding how opioids change the brain makes clear why it is virtually impossible to break the cycle of addiction by sheer force of will." Opioids act by attaching to receptors in the brain and stimulating them to flood the reward system with chemicals that produce intense pleasurable feelings.
When the drugs wear off, they detach from the receptors and strong cravings compel seeking another dose. After as little as a few weeks of use, opiates 'hijack' the brain to the point that it pursues the euphoric effect as it does a basic life need and the compulsion to take more drugs becomes as powerful as the need for food and water. These changes in the brain persist even when drugs are stopped, accounting for continued cravings even after withdrawal. Unless the damage to the brain can be reversed, the individual will be vulnerable to cravings and relapse for many years.
What is medicated-assisted treatment?
Medication-assisted treatment for opioid addiction can alleviate the symptoms of withdrawal, and reduce or eliminate the cravings that would trigger a relapse. Suboxone and methadone are synthetic (man-made) opioids that bind to and activate the same opioid receptors in the brain as the abused drugs but they have different characteristics. They produce a milder "opioid effect" - pleasurable feelings but not the intense highs and subsequent crashing lows that drive users to their next dose. They help the patient avoid the debilitating symptoms of withdrawal that also often short-circuit a commitment to recovery. Vivitrol(an injectable form of naltrexone, administered monthly) is not an opioid but an "opioid antagonist," which means it binds to the same receptors in the brain but does not activate them. It prevents the pleasurable opioid effect and immediately reduces cravings. Vivitrol blocks other opioids from acting on those receptors so if a patient on Vivitrolwere to take another opioid, he or she would not get high, would not get sick, and would not crave the drug.
Is there a down side to medication-assisted treatment?
"Suboxone and methadone do provide a short-term benefit," says Dr. Surasky, "but being themselves opioids they foster dependence and present the long-term challenge of eventual weaning, which may be difficult. And although they prevent cravings, they do not reverse the damage that has been done to the brain and do not allow the brain to reset its emotional temperature. They effectively perpetuate the addictive cycle so patients don't learn coping mechanisms that will enable them to live substance free."
What is the best way to ensure complete recovery?
Dr. Surasky continues: "Vivitrol has these advantages over Suboxone; It is not an opioid, is not addictive, and does not cause physical dependence." By preventing even a mild opioid effect, it enables patients to get reacquainted with their own emotions and focus on behavioral changes without the interference of any mind-altering substance. According to Dr. Surasky, there are newly developed medication protocols that allow patients to be treated with Vivitrol in just a few days rather than the traditional 7-14 days without opiates. This is good news to those suffering with addiction. Suboxone can be useful during that period to reduce withdrawal symptoms. But the best opportunity for a permanent recovery from addiction is an individualized course of treatment with Vivitrolin combination with a strong support program to address the psychological, behavioral, and environmental aspects of the disease." Suboxone®is aregistered trademark of Indivior UK LimitedVivitrol® is a registered trademark of Alkermes, Inc. Russell Surasky, FAAN, ABAM, with Surasky Neurological Center for Addiction, is board certified in both neurology and addiction medicine, is one of the few physicians with this combination of credentials. His primary focus in practice is addiction medicine. Utilizing unique medication protocols individualized to each patient, he provides specialized treatment for opiate, benzodiazepine, and alcohol addiction.


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One of the biggest fear factors whenever you search for a personal injury solicitor, is the question of cost. Will you have to pay fees and if so, will you be left out of pocket should your claim prove unsuccessful? Many people do offer a no-win, no-fee service, but what exactly does that mean? Can you find an injury claim lawyer in Hemingford Abbots who can offer you the kind of service you're looking for?
About no-win, no-fee services
The no-win, no-fee offer is a very familiar one for many people looking to find an injury claim lawyer Hemingford Abbots-based, or indeed, one anywhere else.
However, this is not always what it seems and it is not unheard of for solicitors to advertise themselves as being no-win, no-fee, but slip a few charges in under the radar.
Genuine offers
At Accident Advice Helpline we offer a genuine no-win, no-fee service. This means that you won't have to pay us anything upfront to make a claim on your behalf.
For us we feel that is incredibly important. If no-win, no-fee packages are indeed becoming more rare, then that risks blocking many people from the legal system simply because they feel they cannot afford the fees to make any sort of claim.
Our service also offers all the earliest available information you could want, so that you'll know whether or not you should be making a personal injury claim.
In many cases you'll be best advised not to make a claim at all, as you simply don't stand much chance of winning.
If this is the case we'll tell you very clearly, saving you the time and money involved in making a claim.
Finding an injury claim lawyer in Hemingford Abbots
If we decide that we think you have a good case we will advise you how to take your case forward. Remember – at no stage is there any obligation to choose our firm. We don't have an injury claim lawyer in Hemingford Abbots, but this doesn't matter, nor will it harm your claim.
We feel the advantages are obvious. You don't risk any money and in working this way your solicitor's interests are bound up tightly with your own. So not only will he or she work harder to win the case, but they will also give you more accurate information and advice right the way through the process.
So, to find an injury claim lawyer in Hemingford Abbots, come and talk to us.
For more information you can call us on our freephone number, 0800 689 0500, or ring 0333 500 0993 from a mobile. Call us not and find out more.


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Have you ever wondered what Islam really teaches? Or if the koran is the true word of God? Well today you will get answers to those questions and more as Br. Sam AND Br. Troy share the truth behind Islam !
Special Guest Sam Shamoun, Br. Sam is a frequent contributor to a prominent Web site dedicated to challenging the teachings of Islam. Additionally, he engages in debates as an informed apologist refuting accusations and attacks leveled by proponents of Islam against Christianity.
Special Guest Troy Benjamin was a Muslim for 10 years before being converted to Christanity. Listen to His journey from Islam to Christanity! From the prison system to the Pulpit! Hear how this once fierce enemy of Chrstanity fell in Love with Jesus! We will discuss various topics that are often misunderstood by Muslims. This is definetly a show you will not want to miss!
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Maine Coon kitten. Have fun. Smile! - How to control depression. Wallpaper size 960x640
, combining the appearance of severe beast and fitting
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could hunt and survive in the woods in the harsh winters if they should. Unprecedented Maine Coon able to meow, exceptionally if something is asked, but in their giant arsenal there are other rare sounds, a lot of unparalleled sounds and singular intonations. Most often it is something like the divine cooing, something like "mrrrrr" with distinct exclusive intonations, which they accompany their actions and comments on ours.
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Visual relaxation imagery · Depression treatment · Visual relaxation images
Andrew Karpov
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Jamaica tours Ocho Rios. Large cruise ship being refueled. Ocean liner Ocho Rios Jamaica cruise.
One miraculous Maine Coon
with his whole appearance and behavior inspires awe and admiration, it is characterized by the nobility and a high intellect. Earn His
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Outcome of the Prenatally Diagnosed Congenital Cystic Adenomatoid Lung Malformation: A Canadian ExperienceLaberge J.M.a · Flageole H.a · Pugash D.f · Khalife S.b · Blair G.g · Filiatrault D.c · Russo P.d · Lees G.e · Wilson R.D.h
aDepartment of Surgery, Montreal Children's Hospital, Montreal, bDepartment of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Departments of cRadiology, and dPathology, Hôpital Ste-Justine, Montreal, eDivision of Pediatric Surgery, University Hospital, Edmonton, and Departments of fRadiology, gSurgery, and hObstetrics and Medical Genetics, British Columbia Women's Hospital, University of British Columbia, Vancouver, Canada
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Published online: April 20, 2001
Issue release date: May – June
Number of Print Pages: 9
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ISSN: 1015-3837 (Print)
eISSN: 1421-9964 (Online)
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Congenital cystic adenomatoid malformation of the lung (CCAM) is diagnosed by prenatal ultrasonography with an increasing frequency but controversy persists as to its prognosis and prenatal management. Method: A multi-institutional study of cases of CCAM diagnosed antenatally identified by ultrasonographers and by a review of hospital charts. Results: We obtained 48 cases from five centers. We estimate the incidence of CCAM at 1:25,000 to 1:35,000 pregnancies. The incidence of voluntary abortions was 15% (7/48), of spontaneous abortions 2% (1/41) and of postnatal death 10% (4/40). One of the postnatal deaths was from trisomy 18. Of the 7 aborted fetuses, 2 had multiple malformations and 1 had severe hydrops and oligohydramnios; the other 4 had a large mass with mediastinal displacement but without hydrops. When pregnancy was allowed to continue, 56% of the lesions regressed spontaneously, even though one third of these had initial progression. In 17 cases (42%) the mediastinal shift corrected itself, sometimes by simple growth of the fetus but most often by a decrease in the size of the lung mass. In 1 fetus, repeated needle decompressions followed by double-pigtail catheter drainage of large cysts allowed regression of hydrops. Despite this, neonatal death occurred from pulmonary hypoplasia. Conclusion: CCAM can lead to fetal or neonatal demise from hydrops, lung hypoplasia, prematurity or severe associated malformations, but has a good prognosis in the majority of cases.
© 2001 S. Karger AG, Basel
Article / Publication Details
Published online: April 20, 2001
Issue release date: May – June
Number of Print Pages: 9
Number of Figures: 4
Number of Tables: 2
ISSN: 1015-3837 (Print)
eISSN: 1421-9964 (Online)
For additional information: http://www.karger.com/FDT
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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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University of Glasgow - School of Law
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Roman Law, Civil Procedure
Savigny, Roman law, iudex, precedent, case law
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Roman law, Murecine, Puteoli, Pompeii, civil procedure, vadimonium
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text: Vendeur: 25david (1.684) 99.8%, Lieu où se trouve: Crawley, Lieu de livraison: GB et de nombreux autres pays, Numéro de l'objet: 112059240775 Brand: Booda, MPN: Does not apply, Model: Does not apply, UPC: Does not apply, EAN: Does not apply, Main Colour: Cappuccino, Les Détails: Booda Cleanstep Cat Litter Box Booda Cleanstep Cat Litter Box Description: This innovative cat toilet is both stylish and practical. The Booda Cleanstep Cat Litter Box has plenty of room for digging and scratching, and the cover provides privacy and cleanliness. As the cat leaves the box, the integrated steps in the ramp catch any litter on its paws, keeping the cat and the surrounding area clean.The Booda Cleanstep from Petmate has a spacious interior, with plenty of room for larger cat breeds. The practical high tray design allows you to fill the box with large amounts of litter, and the hooded top design contains any litter scatter, allowing your cat to dig and bury to its hearts content.The Booda Cleanstep Cat Toilet is very easy to clean. The cover features a built-in handle for easy removal and re-assembly. The innovative shape has no corners, making clumps easy to remove.An activated carbon filter in the dome of the box reduces unpleasant odours. This filter should be regularly replaced to keep nasty odours at bay.The modern design and pearlescent colours make this functional, practical litter box a stylish addition to your home, whatever the decor no need to hide the litter box in the corner!The Booda Cleanstep Cat Litter Box from Petmate at a glance:Made in USAInnovative DesignWith steps to prevent litter spreadingCleans paws on leaving the boxRoomy enough for even larger cat breedsHigh tray designNo corners or edges, for easy cleaningBuilt-in handle in coverActivated carbon filter compartment in cover1 activated carbon filter includedDimensions:Diameter approx. 55 cm, Height 50 cmLower tray Height approx.. 15 cmSteps: Width approx.. 23 cmUniversal Active Carbon Filters (x3):Click on product number 320012.3 to receive 3 universal active carbon filters. Their initial size is 20 x 15 x 0.4 cm (LxWxH) but can be cut down to the desired size. When buying replacement carbon filters for this litter box, the filters come 3 to a pack. Booda Cleanstep Cat Litter Box Shipping / Return Policies :Booda Cleanstep Cat Litter Box Shipping Policies:We ship to the UK OnlyWe cannot ship to PO Boxes/APO'sWe cannot combine shipping.No Local Pickup.All items will be shipped directly to you from our supplier within 1-3 business days. Most items are delivered within 3-5 business days, however, please allow 3-10 business days for some larger items..If you have a question about a product not otherwise answered in the item description, please contact us via eBay messages first and allow us the opportunity to help you and be sure we have what you're looking for.Booda Cleanstep Cat Litter Box Exchange/Return Policy:Your satisfaction is guaranteed! If for any reason you are unhappy with your item, just return it within 14 days for a full refund, minus shipping cost. Please contact us prior to initiating a return so that we can issue you a refund authorization.Booda Cleanstep Cat Litter Box Payment PolicyWe require Immediate Payment for Booda Cleanstep Cat Litter Box. Must be an authorized address.


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Luxury and spacious 2-bedroom city-apartment with air condition & two balconys, in walking distance to the historical centre, large public parks and just 5min away from Wien Mitte terminal with a direct airport connection.
This newly renovated apartment (110 sq m) is situated on the 4th floor (easily reachable with an elevator) of a historic building in the center of Vienna.
It has a silent, comfortable courtyard-facing bedroom with a king size bed. The spacious living room contains a pull-out sofa for two & a large flatscreen TV (Amazon Fire with Netflix). Next to the living room is the second bedroom incl. a king size bed (silent room with new sound-proof windows).
The bathroom has a bath tub and a separate shower. The brand-new kitchen is fully equipped with all appliances (including a nespresso machine, dishwasher, induction stove, etc.). There is a washing machine in the utility room. There are two balconys where you can enjoy the sun.
The apartment has a central heating system and a air-condition.
I offer one more apartment in the same building:
17 ความคิดเห็น
เจ้าของที่พักรายนี้มี 57 ความคิดเห็นสำหรับที่พักอื่นดูรีวิวอื่น
Born and raised in Vienna. A few years ago I started my own company which offers background music solutions for hotels, shops and restaurants. Beside that I run a small record label, collect vinyl records and love to travel.


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Contact Suzy on 0151 236 6578
Without an effective marketing strategy most businesses falter and fail. Dental clinics are no different. They exist in a marketplace in which other dental clinics are vying for the attention of their existing and potential customers.
Your most important marketing resource is your existing customer base. By identifying and meeting (and, preferably exceeding) your client's needs, you will create a sales force to be reckoned with.
But single-strategy marketing campaigns rarely succeed in taking a business to new levels of profitability. The most important thing you can do, is carry out research. Find out who your market is, what they want and what they don't want. Build your offer around this information.
Experiment with methods of promotion:
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Remember that marketing is an ongoing concern, not simply a once-in-a-blue-moon, hit-and-run activity. Feedback is crucial: your customers' requirements and expectations can change, and you'll need to shift your offer and the way in which you promote it in order to meet that change successfully. If you don't, you can be certain your competitors will.
Ollie & Darsh 11 Dale Street Liverpool L2 2SH
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text: Help save the Bornean Sun Bear! All proceeds from the sale of these products will be donated to the setting up and funding of the Bornean Sun Bear Conservation Centre (BSBCC) at Sepilok, East Malaysia, where sun bears rescued from captivity will be housed and cared for in natural enclosures before being released, wherever possible, back into the wild. For more information please go to http://sunbears.wildlifedirect.org.


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About This Product
- Sold by
Style: Address Labels
Keep the hand cramps at bay with custom address labels! Our Signature Address Labels are perfect for mailing, labeling, and gift tagging. Add your photos, images, and text to add personal touch to your outgoing sendables. Our address labels are printed in full color and are comparable to Avery® 6871 labels.
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About This Design
Easter Egg Cookies - Boxer
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Jezebel Flirty Bodice Chemise Set Plus Size
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O'Neill, Elaine D. Wilding, John P. H. Kahn, C. Ronald Van Remmen, Holly McArdle, Anne Jackson, Malcolm J. and Close, Graeme L. 2017. Absence of insulin signalling in skeletal muscle is associated with reduced muscle mass and function: evidence for decreased protein synthesis and not increased degradation. AGE, Vol. 32, Issue. 2, p. 209.
Average world life expectancy has seen a dramatic rise over the last two centuries although active life expectancy remains relatively unchanged. One reason for this is that aging results in skeletal muscle becoming smaller, weaker and more susceptible to contraction-induced injury. By the age of 70, muscle strength is reduced by around 30–40% and this can have catastrophic effects on quality of life. Despite a vast amount of research into age-related changes in skeletal muscle, the exact mechanisms responsible for this is still unclear and thus treatments to preserve muscle function with aging remain elusive.
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These authors contributed equally to this work.
Research Article
The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance
Version of Record online: 1 JUL 2013
DOI: 10.1002/emmm.201302827
Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 8, pages 1196–1212, August 2013
Additional Information
How to Cite
Siebzehnrubl, F. A., Silver, D. J., Tugertimur, B., Deleyrolle, L. P., Siebzehnrubl, D., Sarkisian, M. R., Devers, K. G., Yachnis, A. T., Kupper, M. D., Neal, D., Nabilsi, N. H., Kladde, M. P., Suslov, O., Brabletz, S., Brabletz, T., Reynolds, B. A. and Steindler, D. A. (2013), The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO Mol Med, 5: 1196–1212. doi: 10.1002/emmm.201302827
Publication History
- Issue online: 5 AUG 2013
- Version of Record online: 1 JUL 2013
- Manuscript Accepted: 6 MAY 2013
- Manuscript Revised: 2 MAY 2013
- Manuscript Received: 2 APR 2013
- Abstract
- Article
- References
- Supporting Information
- Cited By
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Figure S1. (A) SNAI1, SNAI2 and E-cadherin are expressed in hGBM L0, but not in the other two lines. (B) ZEB1 is the only EMT-associated factor analyzed that affects outcome in the TCGA dataset (REF). (C) ZEB1 is increased at the tumor edge of hGBM L1. Scale bars 10 µm. (D) Tumor mass cells (asterisks) are characterized by membrane-associated beta-catenin, which is absent in invasive cells. Note that invasive cells show no nuclear accumulation of beta-catenin (arrowheads). Scale bars 10 µm.
Figure S2. (A) Beta-catenin is associated with the cell membrane in both control cells (shGFP) and ZEB1 knockdown, while only controls are positive for ZEB1. In addition, control cells appear more dispersed after plating. Scale bars 10 µm. (B) ZEB1 knockdown reduces ZEB1 mRNA levels in tumor-sphere cultures (representative data from hGBM L1, n = 3, t-test). ZEB1 knockdown increases cellular proliferation approximately twofold, whereas forced expression decreases proliferation rates (hGBM L0, n = 3, one-way ANOVA). (C) Threshold images generated from immunofluorescence staining depicted in Figure 2B. These images are used for measuring invasion indices. (D) Putative miR-200c binding sites in the 5′-UTR of c-MYB, SOX2, OLIG2 and CD133.
Figure S3. (A) ROBO1 is preferentially localized at the cell membrane of control cells (shGFP), and absent in ZEB1 knockdown cells. Scale bar, 10 µm. (B) ROBO1 expression is increased by antagonizing miR-200 in ZEB1 knockdown cells, and decreased by forced expression of miR-200 in ZEB1 overexpressing cells. (C) Antagonizing miR-200 increases cell migration (n = 3; Mann–Whitney U-test). (D) ROBO1 knockdown reduces migration in a scratch assay (n = 3, Mann–Whitney U-test). (E) ROBO1 knockdown can be rescued by a non-targeted ROBO1 construct. (F) ROBO1 knockdown reduces tumor invasion in vivo (n = 5 animals each, one-way ANOVA). (G) Forced expression of ROBO1 rescues cell migration in ZEB1 knockdown cells, while ROBO1 knockdown reduces migration in ZEB1 overexpressing cells (n = 3; Mann–Whitney U-test).
Figure S4. (A) Antagonizing miR-200 increases expression of c-MYB and MGMT, as well as chemoresistance in ZEB1 knockdown cells (n = 8, one-way ANOVA). (B) Forced expression of miR-200 reduces expression of c-MYB and MGMT in ZEB1 overexpressing cells, and results in reduced chemoresistance (n = 8, one-way ANOVA). (C) Knockdown of c-MYB reduces expression of MGMT, while overexpression of c-MYB increases MGMT levels. Both have no influence on ZEB1 expression. Resistance to TMZ is significantly reduced by c-MYB knockdown in vitro (n = 8, oneway ANOVA). (D) Chemoresistance in ZEB1-knockdown cells can be rescued by expression of c-MYB (n = 8, one-way ANOVA). (E) Knockdown of c-MYB reduces expression of MGMT and chemoresistance in ZEB1-overexpressing cells. (F) Rescue of MYB, MGMT and ZEB1 knockdown with respective untargeted constructs.
Figure S5. (A) Bisulfite genomic sequencing of the MGMT promoter demonstrates no significant methylation changes in ZEB1 knockdown cells. The MGMT promoter was amplified from −555 to +120 relative to the TSS. The frequency of methylation at each CG site was calculated from at least 10 cloned and sequenced molecules for each condition. Data is presented as the average methylation frequency and the position of each CG site relative to the TSS is indicated. (B) ZEB1 knockdown increases survival of tumor-bearing animals after one cycle (five injections) of TMZ treatment in vivo (log-rank test). Expression of c-MYB in ZEB1 knockdown cells abolished this survival benefit (log-rank test).
Figure S6. (A) ZEB1 negative glioblastoma specimens do not stain for ZEB1 at the tumor invasion front. Scale bar 20 µm (applies to all images). (B) ZEB1, E-cadherin, SNAI1, SNAI2, and Twist-1 are not expressed in glioblastoma specimens. (C) ZEB1 and the proliferation marker Ki-67 are mutually exclusive in tumor specimens (3.66 ± 0.21% co-localization; n = 14; Venn diagrams illustrate overlapping populations of ZEB1 and Ki-67, and ZEB1 and MGMT, respectively). (D) Neither age, nor KPS scores (post-OP or last recorded) correlate with ZEB1, but a significant correlation was found for the ratio of last recorded to post-OP KPS score. (E) PCNA and EGFR are significantly enriched in ZEB1 positive tumor specimens, while loss of NF1 is significantly more frequent in ZEB1 negative samples (Fisher's exact test). (F) Survival analysis for ZEB1 class by molecular subgroups revealed no significant outcome benefit in either subgroup, but shows a general trend for improved outcome in ZEB1 negative tumors. Note the shorter overall survival in the proliferative subgroup (which has the highest percentage of ZEB1+ specimens). (G) TCGA analysis of the ZEB1/miR-200c/c-MYB pathway shows significant changes in patient outcome. Both MGMT and ROBO1 frequently co-occur with ZEB1 in TCGA samples (p-values are from Fisher's exact test). (H) ZEB1 positive samples show higher levels of p-EGFR in RPPA.
Table S1. Clinical information of patient samples used in this study.
Table S2. Vendor information for antibodies used in this study.
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Dear Parents:
My name is Fr. Mariusz Sztuk, SDS and I am delighted to be working with YOU to coordinate the preparation for First Reconciliation, First Holy Communion, and Confirmation this year. The beginning of
the school year also marks the beginning of sacramental preparation. I would like to invite the children to celebrate First Reconciliation and First Holy Communion in their Grade Two or Three and Confirmation in grade 6. The home and parish carry the primary responsibility for this preparation. Enrolment celebration, parent orientation meetings, and sacramental celebrations will originate from the parish. Your involvement and your participation in the parish are crucial to your child's faith development and ultimate commitment to the Catholic faith.
The school instruction regarding the meaning of the sacraments is an essential part of the program. It supports and enhances the learning and the experiences the children encounter at home and in the parish.
The readiness of your child to receive this sacrament will be decided by you in consultation with the pastor.
Your home preparation can begin now. While you await further communication from the parish we encourage you to bring the following points to your child's awareness.
• The fact that she/he may be celebrating a sacrament.
• The name of the sacrament she/he may be preparing to celebrate.
It is also important that as a family you consciously begin your child's preparation for the sacrament by intensifying:
• Your regular participation in Sunday Mass.
• Your daily morning and evening prayer.
• Your daily efforts to imitate the life of Jesus.
All classes will be held at Our Lady of Wisdom School (OLOW), and will start at 6:00 p.m. on Thursdays (Except for Registration Meeting 5:30 p.m.). Costs for this process are approximate $30.00 per child to offset the costs of the child's book and parental background materials.
The registration will take place during the first meeting,
• September 14th at OLOW School at 5:30 p.m. Sacrament of Confirmation
• September 21th at OLOW School at 5:30 p.m. First Reconciliation
• September 28th at OLOW School at 5:30 p.m. First Holy Communion
• Please register online at: http://www.saintgabrielparish.ca
• Please mark these dates in your calendar. They will also be published in the weekly church bulletin.


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Copiah-Lincoln Community College biomedical engineering
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Find information about Copiah-Lincoln Community College biomedical engineering, and registering for elective courses. Which college degrees give you the best chances of finding employment after graduation? Engineering job offers command high salaries due to accelerating technical innovation in manufacturing and heavy industry. Concentrating on Copiah-Lincoln Community College biomedical engineering, for example, you may gain an advantage in job recruiting on-campus. Check with the biochemical engineering department for course registration deadlines, and genetic engineering program requirements. Please use the form above to request admissions info for Copiah-Lincoln Community College.
Biotechnology uses the DNA of living organisms to bioengineer new products artificially. Depending on the tools and applications, it often overlaps with the related fields of biomedicine, pharmacology, and genetic engineering. Modern biotech methods are used to manufacture existing medicines more easily, in order to treat human diseases. Further, biotechnology has enabled emerging techniques like gene therapy. Stem cell research offers new hope in the areas of cancer treatment as well as life extension. The regulation of genetic engineering aims to assess and manage the risks of developing genetically modified organisms (GMO), including commercial food crops and fish.
At the smallest scale, mechanical engineering becomes nanotechnology, one goal of which is to build molecules and materials via microsynthesis. Current areas of mechanical engineering research in biotech and nanotechnology include nanofilters, nanofilms, and nanostructures such as microtubules. Self-assembly of these structures may lead to new breakthroughs in artificial tissue generation. Micron-scale mechanical components such as springs, gears, and heat-transfer devices are fabricated from a variety of substrate materials such as silicon, glass and polymers like SU8. Biomechanics applies traditional engineering methodology to the analysis of biological systems. By copying the efficiency of nature, the study of biomechanics aids in creating prosthetic limbs and artificial organs for medical application. Beyond major requirements within the biochemical engineering department, you may consider Alfred University electrical engineering as an adjunct to your primary course of study.
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This creative portfolio is just too big to be viewed on a tiny screen!
Try rotating your phone to landscape mode, or, even better, view on a tablet or computer screen.
"Design, good or bad, is a vehicle of memory. It is easier to remember a well-designed image than one that is muddled. A well-designed logo, in the end, is a reflection of the business it symbolizes." -Paul Rand
Your logo represents your company to your consumers and serves as an identifier to which your consumers even sometimes become loyal. Your logo is a visual expression of your company, product or service, and should derive its meaning accordingly - not the other way around.
I love the challenge of creating new customer experiences and have collaborated with many in designing compelling and effective campaigns to highlight a wide variety of products and services. Want to work together? Drop me a line!


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Passionate about new technologies, I'm always on the lookout for new possibilities. I started out as a web programmer and then evolved to a project manager, to finally become coordinator of my team. I work for a non-profit organisation in which I coordinate the work of a multi-disciplinary team, from programmers to designers. In my free time, I like to go fishing and relax.
English session - Intermediate
CSS is becoming more and more powerful and nowadays it allows a lot of possibilities. This talk is a compilation examples for more advanced tips and techniques to add to your CSS skills. Have you ever wanted to curve text around a floated image? Or maybe style broken images? How about using attribute selectors more effectively? Then this talk is for you.
English session - Beginner
Varnish is an open source, high performance http accelerator that sits in front of a web stack and caches pages. It is highly configurable and can be used for static or dynamic content equally. It can improve the performance of your website without requiring any code changes. If you haven't heard of Varnish, or have heard of it, but haven't used it, This talk is for you! This talk will guide you through configuring Varnish for the first time.


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Samsung Galaxy Note 8 2017 Series
The rumors about the Samsung Galaxy Note 8 do not stop, and it is that This is one of the most anticipated of the year phones. If we already liked the Samsung Galaxy S8, imagine a version with dual camera, can not go anything wrong. Today, we have new news on this terminal, which we are sure that you will love.
It is almost confirmed that Samsung Galaxy Note 8 will have a dual camera, but was unknown so far the operation of the same. Today, we bring you news about how to operate the cameras of Note, so stay with us.
Samsung Galaxy Note 8 Camera
Also speaks that will be able to zoom 3 X optical form, which would be quite well since the current standard of the optical zoom is 2 x. There is nothing confirmed yet, but we are convinced that the portrait mode is something that will come to Samsung since the public demand it more and more.
If Samsung met expectations, we are, next to the Google Pixel 2, one of the best, or the best Android camera. Time will tell, and patience, because already there is less so that this beast is presented.
More or less a week ago that we knew some of the developments that would offer us the new Samsung ISOCELL dual sensor, the call to become Note 8 dual camera sensor. As well, they have today transcended new data on this dual sensor that will feed the dual camera of Samsung Galaxy Note 8. In the filtered slide, you can see the four main features of the new photo chip Samsung.
The first one is a greater brightness, something that no doubt has characterized Samsung cameras, which capture light in the worst conditions. As well as its speed, thanks to the Dual Pixeltechnology, it also highlights its small pixels, which allow a more slim design, and finally the most interesting feature, as it is the dual camera and an interesting function, as it is the so-called Depth Sensing.
This function, which is a complete unknown could hide after Yes one of the major innovations of Samsung Galaxy Note 8. This technology could offer the same features as Google's Project Tango, so thanks to her Samsung Galaxy Note 8 camera could create 3D images of our environment thanks to the ability of the new chip ISOCELL recognize the depth and volume of objects that surround us. It would certainly be a great novelty that could revolutionize the launch of the new Samsung Galaxy Note 8.
All expect a great camera's 8 Note, but no doubt this ability to be able to map 3D environments could be key for Samsung signed up the growing industry of augmented reality, which is also working on Apple and who knows, could also offer 8 iPhone camera. In any case it will not touch us wait more than two months to see if these characteristics are reflected in Note 8 camera.
Source: galaxy note 8 2017


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Software Engineer - Trading Technology - New York
- USD120000.00 - USD175000.00 per year + Bonus
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- 18 Sep 17
Establish fintech firm in the city are looking for multiple engineers to support a growing business.
An established Fintech firm in the city, focused on building best in class trading technology, are looking for bright junior and mid-level engineers. This firm has a single office, situated in the beating heart of Manhattan, where all of their development takes place. Every engineer in that office has a daily impact on the future of the firm.
This firm has a predominantly Java-centric code base, but have a pipeline of projects that will leverage a range of technologies including Scala, Go, Javascript (with the latest frameworks) and bleeding edge streaming technologies.
Ideal candidates will have...
- Anywhere between 1 and 6 years of development experience
- A STEM degree, preferably computer science
- Rock solid computer science fundamentals (Algos, Data structures, Design patterns)
- Good communication skills
This is a an excellent firm with a very strong engineering culture. The leaders are focused on building the best possible systems with the best available tools. Great culture, excellent perks, very friendly environment, very cool office.
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