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INTRODUCTION — Infantile hemangiomas are benign tumors of vascular endothelium [1,2]. They are the most common tumors of childhood. They are characterized by a growth phase and involution phase. Despite their benign and self-limited nature, some hemangiomas can cause complications such as ulceration or life-altering disfigurement. In addition, they may compromise vital organ function or herald underlying developmental anomalies of the central nervous system or spine. Infants with cutaneous hemangiomas, most often in the setting of multiple hemangiomas or a solitary segmental hemangioma, occasionally have additional hemangiomas of the liver, brain, respiratory tract, or gastrointestinal tract. Rarely, visceral hemangiomas can be symptomatic and associated with life-threatening complications.
The management of infantile hemangiomas will be discussed below. The epidemiology, pathogenesis, clinical features, complications, and evaluation are discussed separately. Other vascular tumors of childhood are also discussed separately.
●(See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)
●(See "Evaluation and diagnosis of infantile hemangiomas".)
●(See "Rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH)".)
●(See "Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon".)
GENERAL APPROACH — The approach to treatment of hemangiomas should be individualized, based upon the size of the lesion(s), morphology, location, presence or possibility of complications, potential for scarring or disfigurement, the age of the patient, and the rate of growth or involution at the time of evaluation [3,4]. The potential risk(s) of treatment must be carefully weighed against the potential benefits.
Consultation with and/or referral to a pediatric dermatologist, vascular anomalies team, or other knowledgeable specialist is warranted for children with hemangiomas with actual or potential risk for complications and/or when therapy is being considered [5]. Such children should be referred as early as possible during the early proliferation phase (ie, during the first few months of life).
Hemangiomas are managed with clinical examination(s) and education of the family regarding the natural course; potential complications; treatment indications; and risks, benefits, and expectations of available treatment options. Depending upon the type of lesion and the parents' level of concern, the patient may need to be re-evaluated frequently during the proliferative phase and again before school entry. Serial photographs of the lesion can help to monitor the clinical course.
Education of the family should include information about the natural course; potential complications; treatment indications; and risks, benefits, and expectations of available treatment options for hemangiomas. The family should be provided with realistic expectations about the duration of involution and the possibility of residual changes. The involution phase may continue up to the age of 10 years, although in some studies complete involution has been noted at a median age of four years [6,7]. However, this timeline is highly variable and dependent on hemangioma size, morphology, and location. It must also be emphasized that, in many cases, involution does not result in normal-appearing skin. More than one-half of children with untreated hemangiomas experience residual changes such as scarring, atrophy, redundant skin, discoloration, and telangiectasias [8].
Finally, the family should be provided with anticipatory guidance regarding ways to respond to comments and queries from family members and strangers. Parents are commonly subject to inappropriate comments from strangers, including accusations of child abuse [9]. Other children, who are usually extremely curious about the hemangioma, are often satisfied to know simply that "It is a birthmark, it doesn't hurt, and it will get better" [9]. Addressing the psychosocial aspects of care and providing the parents anticipatory guidance, emotional support, and reassurance are essential for the effective management of hemangiomas [3,9-11].
When treatment is indicated, the choice of treatment modality depends upon the above factors, as well as the availability of certain modalities and the experience of the treating clinician.
INDICATIONS FOR INTERVENTION AND GOALS OF TREATMENT — Intervention may be required for complicated lesions with potential to interfere with a vital structure or function [1]. These include, but are not limited to:
●Very large, rapidly growing cutaneous hemangiomas
●Lesions in the periorbital region
●Lesions in the airway, liver, or gastrointestinal tract
In addition, intervention may be indicated for lesions associated with other complications such as ulceration and/or increased risk of scarring or disfigurement [12]:
●Large, plaque-like (segmental) or nodular hemangiomas, especially in trauma-prone locations, have a tendency toward ulceration, which invariably leads to scarring.
●Any lesion of the face, especially when large or segmental; hemangiomas of the lip (picture 1), nose ("Cyrano nose"), and auricle are particularly prone to disfigurement.
●Large, nodular, superficial hemangiomas, especially those that exhibit a sharp, "cliff-like" border (picture 2), or pedunculated lesions (hemangiomas extending from a small base) have the greatest risk of scarring. These lesions are also at risk for leaving residual fibrofatty tissue that may require surgical revision.
The goals of hemangioma treatment include [3]:
●Prevention or reversal of life-threatening or function-threatening complications
●Prevention or minimization of disfigurement from residual skin changes
●Minimization of psychosocial distress for the patient and family
●Adequate treatment of ulceration to minimize scarring, bleeding, infection, and pain
Active nonintervention — Active nonintervention (serial observation) is the mainstay of therapy for many uncomplicated, localized hemangiomas because hemangiomas involute spontaneously after the first year of life. However, the decision not to pursue medical and surgical therapy is not necessarily a passive intervention, since the growth and involution of the hemangioma may need to be monitored and the psychosocial implications, particularly of facial hemangiomas, anticipated and addressed [9]. Serial photographs of the lesion may be helpful to monitor the involution process and outcome.
Local therapies — Local pharmacotherapy is primarily used in the treatment of small or superficial infantile hemangiomas and is not indicated for the treatment of complicated lesions. Data on the efficacy of topical therapies, including topical beta blockers, corticosteroids, and imiquimod, are limited.
Topical beta blockers — Reports of successful treatment of hemangiomas with systemic propranolol led to the investigation of topical beta blocker therapy for the treatment of infantile hemangiomas [13,14]. Topical beta blockers may be used for the treatment of small superficial hemangiomas (eg, hemangiomas of minor cosmetic concern located on the face, small lesions in the anogenital area) as an alternative to observation, particularly if parents desire treatment. Topical beta blockers may also have a role in the treatment of small ulcerated hemangiomas and in preventing rebound growth in children who are being tapered off oral propranolol [15]. (See 'Rebound growth' below and 'Ulcerated hemangiomas' below.)
If a decision is made to use topical beta blockers, we use topical (ophthalmic) timolol gel-forming solution 0.5%. One drop is applied two to three times per day for 6 to 12 months or until stable improvement is achieved.
Efficacy — The efficacy of topical propranolol 1% (not available in the United States) or topical timolol 0.5% has been confirmed by a systemic review and meta-analysis and a large retrospective cohort study [16,17].
●In a 2015 systemic review and meta-analysis of 14 cohort studies and three randomized trials, the pooled response rate was approximately 80 percent for both topical propranolol and topical timolol [16].
●In a subsequent large multicenter retrospective cohort study, 731 children with predominantly superficial hemangiomas were treated with topical timolol 0.5% twice daily [17]. The primary outcome measure was efficacy assessed by using visual analog scales for color and for size, extent, and volume from review of digital photographs. After six to nine months of therapy, 92 percent of patients showed significant improvement in color and 77 percent in size, extent, and volume.
Safety — Topical timolol is generally well tolerated. However, data on its safety are limited.
●In a retrospective study, 22 high-risk infants (young or preterm infants, infants receiving more than two drops/day, or infants receiving application to a site with potential increased systemic absorption) with hemangiomas predominantly located in the periocular area were treated with topical timolol and received continuous cardiac monitoring (Holter) for at least 24 hours [18]. Two infants developed symptomatic bradycardia associated with apnea or hypothermia requiring discontinuation of timolol; both were preterm (weighing <2500 grams) and had a history of symptomatic bradycardia prior to the initiation of timolol treatment.
●In another study including 40 children of 2 to 35 weeks of age with superficial or mixed-type hemangiomas (nine ulcerated), no bradycardia or changes in pulse rate were detected during treatment with topical timolol gel 0.5% twice daily [19]. Systemic absorption of timolol was examined in a subgroup of 24 children. Timolol was detected in the urine of 20 children and in the serum of all tested children, although serum levels were too low to cause systemic symptoms.
●In a large multicenter retrospective study, 731 children with hemangiomas predominantly superficial and located in the head/neck area were treated with topical timolol 0.5%, one drop twice daily, for an average of 9.5 months [17]. Adverse effects occurred in 25 (3.4 percent) patients, including local irritation (n = 12), ulceration (n = 4), and bronchospasm (n = 3). None of the children experienced cardiovascular adverse effects or required drug discontinuation.
Topical and intralesional corticosteroids — High-potency topical corticosteroids (eg, clobetasol propionate cream) have been used in the past for small, superficial hemangiomas at risk for ulceration or small periocular lesions [20]. They are now infrequently used since the introduction of topical timolol. In the author's experience, topical corticosteroids may be helpful for the treatment of minor but recurrent ulcerations. Adverse effects of long-term use of topical corticosteroids include skin atrophy, hypopigmentation, and hypertrichosis.
The use of intralesional corticosteroids such as triamcinolone acetonide 10 to 40 mg/mL is limited to small, well-localized, deep hemangiomas [21]. Individual doses should not exceed 3 mg/kg. A response usually is noted within two weeks, with continued response over the ensuing six to eight weeks [22]. Serial injections administered at four-week intervals are sometimes needed. Adverse effects of intralesional corticosteroids most commonly include local skin atrophy from leaks or inadvertent application to normal surrounding skin. Adrenal suppression from systemic absorption is also a possibility, even with localized use [23-25].
Imiquimod — Imiquimod is a topical immune response modifier with antiangiogenic and proapoptotic properties [26]. There are no randomized trials evaluating the efficacy of imiquimod for the treatment of infantile hemangiomas, and results from observational studies and case reports are conflicting [27-32]. Until further studies are available, the decision to prescribe imiquimod should be carefully weighed against active nonintervention and other treatment options for individual patients [33].
COMPLICATED HEMANGIOMAS — Complicated hemangiomas that require treatment include large hemangiomas at increased risk of scarring or disfigurement (eg, large or segmental hemangiomas, facial hemangiomas), life-threatening hemangiomas (eg, airway hemangiomas), hemangiomas carrying functional risks (eg, periocular hemangiomas), or hemangiomas with severe ulceration. (See 'Special situations' below.)
Propranolol — Propranolol, a nonselective beta blocker, is the first-line agent for hemangiomas with the potential to impair function or cause permanent disfigurement, if there are no cardiac or neurovascular concerns [1,34]. In 2014, propranolol hydrochloride oral solution was approved by the US Food and Drug Administration for the treatment of proliferating infantile hemangioma requiring systemic therapy [35].
Propranolol inhibits the growth and induces the regression of infantile hemangiomas [36]. Potential mechanisms of action for propranolol may include vasoconstriction, decreased expression of vascular endothelial growth factor and basic fibroblast growth factor, and/or triggering of apoptosis [37,38].
Efficacy — In 2008, the serendipitous observation that the use of propranolol to treat heart failure in two young children with infantile hemangiomas was associated with a change in color, softening, and decrease in size of the hemangiomas led to the initiation of larger observational studies and randomized trials. All studies demonstrated improvement with propranolol [36,39-45].
●In a large, industry-sponsored, randomized trial, 456 infants aged five weeks to five months with a proliferating hemangioma of at least 1.5 cm received placebo or propranolol (1 mg/kg per day or 3 mg/kg per day) for three or six months [45]. The primary outcome was complete or nearly complete resolution of the hemangioma at week 24, assessed by centralized blinded evaluation of digital photographs. Complete or nearly complete resolution of the target hemangioma was observed in 60 percent of patients treated with propranolol 3 mg/kg per day for six months and 4 percent of those treated with placebo. Ten percent of patients in whom treatment was successful required systemic retreatment during follow-up. Mild adverse effects, including diarrhea, sleep disorders, bronchial hyperreactivity, cold extremities, upper respiratory tract infection, and fever, occurred in over 90 percent of patients receiving propranolol and 76 percent of those receiving placebo. Serious adverse events suspected to be related to propranolol were rare (occurred in single patients only) and included second-degree atrioventricular block, bronchiolitis, hemangioma worsening/ulceration, and bradycardia.
●A network meta-analysis of 18 randomized trials and cohort studies including 1265 children aged two weeks to nine years evaluated the relative expected rates of clearance associated with beta blockers and corticosteroids [46]. Oral propranolol in doses ranging from 1 to 4 mg/kg per day had the largest mean estimate of expected clearance (95 percent, 95% Bayesian credible interval [BCI] 88-99), relative to oral corticosteroids (43 percent, 95% BCI 21-66) and placebo or observation (6 percent, 95% BCI 1-11).
Oral propranolol has also been used to treat infantile hemangiomas beyond the proliferative phase [47,48]. In a multicentric, retrospective study, 42 children aged 7 months to 10 years with documented cessation of hemangioma growth were treated with propranolol 1.5 to 3 mg/kg per day for one to eight months [47]. In all children, the rate of involution increased with propranolol compared with the rate of involution during active nonintervention before treatment.
Administration — The use of propranolol for the treatment of complicated infantile hemangiomas is illustrated in the algorithm (algorithm 1).
Pretreatment evaluation — Treatment with propranolol should be undertaken in consultation with a pediatric dermatologist or other specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and use of propranolol in children (algorithm 1). The pretreatment evaluation (inpatient or outpatient) should include:
●History, with focus on cardiovascular and respiratory abnormalities (eg, poor feeding, dyspnea, tachypnea, diaphoresis, wheezing, heart murmur) and family history of heart block or arrhythmia.
●Physical examination including cardiac and pulmonary assessment and measurement of heart rate and blood pressure. However, since obtaining accurate blood pressure readings in infants is difficult, blood pressure measurement should be attempted only if there is suspicion of underlying cardiovascular disease. (See "The pediatric physical examination: General principles and standard measurements", section on 'Vital signs'.)
●Electrocardiogram in children with:
•Heart rate lower than normal for age
•History of arrhythmia or arrhythmia detected during examination
•Family history of congenital heart disease or maternal history of connective tissue disease
●Imaging studies, including cardiac ultrasound or cardiac magnetic resonance imaging (MRI), should be obtained in children with large facial hemangiomas at risk for PHACE to rule out the possibility of severe aortic coarctation, which is a contraindication to propranolol use. In these patients, baseline head/neck MRI with angiography is also preferred prior to propranolol initiation, unless the clinical situation requires urgent treatment (eg, severe visual obstruction due to an orbital hemangioma). In such cases, propranolol can be initiated at a lower dose and slowly titrated up to a maximum dose of 1 mg/kg/day.
Contraindications — Propranolol treatment is contraindicated in infants and children with:
●Cardiogenic shock
●Documented chronic and significant sinus bradycardia
●Documented chronic and significant hypotension
●Greater than first-degree heart block
●Heart failure
●History of bronchospasm or wheezing
●Hypersensitivity to propranolol
●Preterm infants with corrected age <5 weeks (postnatal age in weeks minus number of weeks preterm)
Initiation of treatment and dosing — In most cases, treatment can be initiated in an outpatient clinical setting by a clinician with experience in the diagnosis and management of infantile hemangiomas (algorithm 1). Every dose increase should also be administered by an experienced clinician in an outpatient setting. However, in accord with an expert consensus panel, we suggest that hospitalization for initiation of oral propranolol be considered in the following circumstances [34]:
●Infants ≤5 weeks of age
●Preterm infants with corrected age ≥5 weeks (postnatal age in weeks minus number of weeks preterm)
●Infants of any age with inadequate social support
●Infants of any age with comorbid conditions affecting the cardiovascular or respiratory system, including symptomatic airway hemangiomas
●Infants of any age with conditions affecting blood glucose maintenance
We generally start treatment with oral propranolol at 0.5 to 1 mg/kg per day in two or three divided doses with feeds. If tolerated, the dose is then gradually increased (ie, in increments of 0.5 mg/kg per day) over one to two weeks to the target dose of 2 mg/kg per day, given in two or three divided doses with feeds. Administering propranolol with feeds reduces the risk of hypoglycemia.
In case of intercurrent illness associated with vomiting, diarrhea, and/or poor feeding, treatment may be temporarily held and then resumed at the last given dose. If children present with respiratory symptoms or wheezing, propranolol should be temporarily held and then resumed at a lower dose and titrated up more gradually to a lower target dose (less than 2 mg/kg/day). (See 'Adverse effects' below.)
Monitoring — Since the effect of oral propranolol peaks at one to three hours after administration, an expert consensus panel has recommended that patients be monitored with measurement of heart rate and blood pressure at one and two hours after the initial dose and after every dose increase of 0.5 mg/kg/day [34]. However, in clinical practice, many experts (including the author) do not monitor heart rate and blood pressure in clinic after the first dose and after dose increases (algorithm 1) [49].
Parents should be educated about recognizing signs of serious adverse effects, which include hypotension, bradycardia, wheezing, and hypoglycemia [50]. Early clinical signs of hypoglycemia include:
●Poor feeding
All of these clinical signs may be masked by beta blockers except sweating. Thus, sweating may be the most reliable early sign of hypoglycemia to watch for.
Routine screening of serum glucose is not indicated because the timing of hypoglycemic events is variable and unpredictable. In addition, asymptomatic hypoglycemia was not detected in studies that included a random serum glucose as part of routine monitoring [34].
●(See "The pediatric physical examination: General principles and standard measurements", section on 'Heart rate'.)
●(See "Evaluation and diagnosis of hypertension in infants between one month and one year of age", section on 'Blood pressure measurement'.)
●(See "Approach to hypoglycemia in infants and children", section on 'Clinical features'.)
Assessment of response and treatment duration — Children with infantile hemangiomas treated with propranolol should be followed up at one- to three-month intervals for response assessment and dose adjustment for weight gain. The duration of treatment typically ranges between 6 to 12 months (or until the child is a 12- to 18-month-old), but may be longer, depending upon the size and location of the hemangioma and response to treatment.
Although a significant response (reduction in size or nearly complete resolution) is generally seen after three to four months of propranolol treatment, some experts continue therapy until the child reaches the age in which the spontaneous involution phase would normally begin [1]. This typically occurs around one year of age, but may occur earlier or later depending on the hemangioma size.
Lack of response to treatment with propranolol is rare. In a French retrospective, multicenter study including 1130 children treated with propranolol, 10 (0.9 percent) had propranolol-resistant hemangiomas [51]. Resistance was defined as continued growth during the proliferative phase or no involution during the postproliferative stage after >4 weeks of oral propranolol at greater than 2 mg/kg per day. Five of the 10 children who did not respond to propranolol had hemangiomas in the postproliferative stage and were older than eight months at the start of treatment. Three children with hemangiomas in the proliferative stage showed a rapid response to adjuvant systemic corticosteroids.
Rebound growth — Rebound growth after propranolol discontinuation has been noted in approximately 14 to 25 percent of children [52-54]. The factors associated with the risk of relapse are not completely understood.
Some children with rebound growth may need a second course of propranolol. Topical beta blockers may be used to treat mild to moderate relapses. However, in most cases mild relapses do not require treatment and parents can be reassured about the eventual involution of the lesion.
In a single-institution study including 158 children with hemangiomas located predominantly in the head and neck region who were treated with propranolol for 3 to 12 months, a relapse occurred in 40 (25 percent) 0.5 to 5 months after treatment cessation [54]. In half of them, the relapse was mild and did not require retreatment. Factors associated with an increased risk of relapse included segmental distribution and depth of the hemangioma.
Adverse effects — Serious adverse effects of propranolol therapy for hemangiomas, which include hypotension, bradycardia, hyperkalemia, bronchospasm, and hypoglycemia, are infrequent [45,55,56]. Restless sleep, constipation or diarrhea, and cold extremities are more commonly reported [56]. Thus, children treated with this drug should be closely monitored.
In a review of 906 French children (median age 114 days) treated with propranolol for complicated hemangiomas, one or more adverse reactions occurred in 81 (9 percent) [57]. Serious adverse effects occurred in 24 patients (2.6 percent) and included cardiac adverse events in two patients, respiratory adverse events in nine, and hypoglycemia in four. Common adverse effects included sleep disturbances, acrocyanosis, and diarrhea.
Of the potential serious adverse effects, hypoglycemia is the most worrisome. To reduce this risk, propranolol should be administered during the daytime hours with a feeding shortly before or after administration. Propranolol should be discontinued during periods of illness or poor oral intake [34,50,58].
Patients who may be at increased risk for propranolol-induced hypoglycemia include children under the age of one year (especially low-birth-weight infants), patients who were previously treated with prolonged courses of systemic glucocorticoids, and patients with high-output cardiac failure secondary to a large liver hemangioma [58,59]. However, symptomatic hypoglycemia during propranolol use has also been reported in older children [58].
Other beta blockers — A few small trials suggest that nadolol and atenolol may be as effective as propranolol for the treatment of proliferative hemangiomas, potentially with a lower rate of adverse effects such as bronchoreactivity and sleep disturbances [60,61]. However, these findings are preliminary and need to be confirmed by larger trials.
Systemic corticosteroids — Treatment with systemic corticosteroids for complicated hemangiomas has been largely supplanted by systemic beta blockers. However, systemic corticosteroids remain a treatment option for patients with complicated hemangiomas for whom treatment with beta blockers is contraindicated. (See 'Contraindications' above.)
Systemic corticosteroids were compared with propranolol in a small, noninferiority, randomized trial [62]. In this study, 34 children aged 0.3 to 8.2 months with hemangiomas located predominantly on the face were randomly assigned to treatment with propranolol 2 mg/kg per day in three divided doses or prednisolone 2 mg/kg/day in a single dose for 16 weeks. A response to treatment, broadly defined as stop of progression and volume decrease, was achieved by 96 and 92 percent of patients in the propranolol and systemic corticosteroid groups, respectively. Adverse effects were generally mild and occurred with equal frequency in both groups.
Dosing — The usual starting dose for prednisolone is 2 to 3 mg/kg per day, although some clinicians advocate higher starting doses of up to 5 to 6 mg/kg per day. A single, morning dose is preferred to minimize adrenal suppression. A response (stabilization with or without regression) is usually seen within the first few weeks [63,64]. Treatment is generally continued for several months or more, depending upon the indications for treatment, the response, and the child's age at initiation [11]. Prednisone should be slowly discontinued since abrupt discontinuation or rapid tapering of glucocorticoids while a hemangioma is still in its active growth phase may result in rebound proliferation [10].
Adverse effects — Adverse effects of systemic corticosteroids are more likely to develop with higher doses and courses of six months or longer and resolve with drug tapering.
●The most common complication is the development of a cushingoid facies, which usually begins within the first one to two months of treatment [65].
●Personality changes (eg, depressed mood, agitation, insomnia, restlessness) develop in approximately one-third of infants, usually during the first two weeks of therapy [65].
●Delayed skeletal growth, which may be more readily apparent since a child grows most rapidly during the first year of life, results from a temporary inhibition of collagen synthesis. However, nearly all children catch up to the normal growth curve once therapy has been discontinued, usually by two years of age [65,66].
●Gastric upset occurs in at least 20 percent of infants and can be relieved with histamine 2 (H2) blockers, such as ranitidine hydrochloride, which many initiate routinely along with glucocorticoids [65].
●Serious corticosteroid complications, such as aseptic necrosis of the femoral head, hypertension, osteoporosis, and cataracts, are extremely rare in children [65].
Systemic corticosteroids have immunosuppressive effects and can increase the risk for infections [67]. There are at least two reports of Pneumocystis carinii pneumonia (PCP, but officially renamed Pneumocystis jirovecii pneumonia) developing in infants treated with glucocorticoids for hemangiomas [68,69]. While the true risk of PCP and the utility of antibiotic prophylaxis in this population are not known, some advocate that trimethoprim-sulfamethoxazole prophylaxis be considered [67], particularly in infants with airway involvement or other risk factors for PCP [68].
We do not routinely administer PCP prophylaxis to children being treated with systemic glucocorticoids for infantile hemangiomas. However, PCP prophylaxis may be warranted in infants who have other risk factors for PCP (eg, premature infants with significant concomitant medical problems). (See "Glucocorticoid effects on the immune system" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in HIV-uninfected patients".)
Live-virus vaccines (eg, measles, mumps, rubella [MMR], varicella, rotavirus), should not be administered while infants are taking supraphysiologic glucocorticoid doses. In addition, because the varicella vaccine is not administered until children are at least one year of age, infants receiving glucocorticoid therapy should avoid exposure to individuals with varicella infection. (See "Standard immunizations for children and adolescents", section on 'Overview'.)
Immunization for diphtheria and tetanus may not be effective in some patients when administered during systemic glucocorticoid therapy [67]. Diphtheria and tetanus titers can be used to confirm protection.
Supraphysiologic doses of glucocorticoids may suppress the hypothalamic-pituitary-adrenal axis. "Stress doses" of glucocorticoids may be necessary for infants who require medical or surgical hospitalization while undergoing glucocorticoid therapy for infantile hemangiomas [70].
Other systemic therapies — Vincristine and interferon alpha are alternative systemic agents for the treatment of complicated hemangiomas but are rarely used since the advent of propranolol.
●Vincristine – Vincristine is used in the treatment of the Kasabach-Merritt phenomenon associated with the kaposiform hemangioendothelioma and tufted angioma [71,72] (see "Tufted angioma, kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon"). Its use has expanded to include more aggressive hemangiomas as an alternative therapy for life-threatening or severely life-altering hemangiomas unresponsive to propranolol or corticosteroids.
Vincristine is generally administered by a central venous catheter. Its administration is commonly overseen by a pediatric hematologist/oncologist [73-75]. Toxicities of vincristine include peripheral neuropathy, constipation, jaw pain, and rarely leukopenia and anemia.
●Interferon alpha – Interferon alpha, a potent inhibitor of angiogenesis, has been used in the past as an alternative therapy for aggressive hemangiomas not responsive to glucocorticoids [4,76-78]. The initial dose of interferon alpha is 3 million units/m2 per day [3]. The interval between administration and response ranges from a few weeks to several months [11].
Adverse effects of interferon alpha that are usually transient include fever, irritability, neutropenia, and liver enzyme abnormalities [63]. The most worrisome adverse effect of interferon is severe neurotoxicity, including spastic diplegia.
In one meta-analysis including 441 infants with vascular lesions treated with interferon, 11 (2.5 percent) developed permanent spastic diplegia and 16 (3.6 percent) motor developmental complications that reversed upon discontinuation of therapy [79]. Because of this concerning adverse effect, interferon alpha is rarely used for the treatment of infantile hemangiomas.
Surgical therapies — When a hemangioma poses primarily cosmetic concerns, therapeutic intervention must be tailored on an individual basis. In addition to systemic, topical, and intralesional medications, therapeutic options include laser therapy and surgery. Cautery, irradiation, and cryotherapy may produce more scarring than untreated lesions and are thus not generally recommended.
Pulsed-dye laser — The pulsed-dye laser (PDL) cannot be expected to affect hemangiomas with deep involvement, since the depth of laser penetration is only 1.2 mm. The most accepted use of PDL in the management of hemangiomas is the treatment of ulceration, post-involution erythema, and/or telangiectasias [4]. Which hemangiomas benefit most from laser therapy and what the optimal settings are remain areas of controversy [80]. Indications, efficacy, and adverse effects of PDL therapy for infantile hemangiomas are discussed in detail elsewhere. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Infantile hemangiomas'.)
Excisional surgery — Surgical excision is often reserved for involuted lesions with residual scars or loose skin; hemangiomas no longer involuting after age four; pedunculated cutaneous hemangiomas (because of the risk of scarring); small, localized periorbital hemangiomas; and slowly involuting lesions in cosmetically concerning locations [6,63,81]. Excisional surgery may also be considered for large periocular hemangiomas, refractory ulcerated hemangiomas, and nasal-tip hemangiomas, but only if medical therapy is thought to pose a greater risk and the resultant scar is likely to be acceptable. In cases without complication, but for which there is uncertainty about the outcome, the benefits and risks of surgical intervention must be carefully considered since the surgical scar may be worse than the results of spontaneous involution [64,82].
Embolization — As a last resort, large visceral (especially hepatic) hemangiomas have been treated with arterial embolization after failure of medical therapy [81]. The results may be temporary.
Periocular hemangiomas — Periocular hemangiomas can compromise vision and cause amblyopia, astigmatism, or strabismus. These hemangiomas should be evaluated by an ophthalmologist experienced with hemangiomas and their treatment [22]. Recommendations may include patching the unaffected eye to ensure that the partially obstructed eye is used. Superficial periocular hemangiomas have been successfully treated with topical beta blockers [13,83]. Surgical excision also may be an option for small, localized lesions [84-87].
Vision-threatening cases are generally treated systemically with propranolol or, less commonly, with intralesional corticosteroids [21,40,88-91]. Intralesional corticosteroids should be managed by a specialist, most often an ophthalmologist with knowledge and experience in this area. Rare but serious side effects, including eyelid necrosis, central retinal artery occlusion, and adrenal suppression, have been reported [92-96].
Ulcerated hemangiomas
Wound care — Gentle and meticulous local wound care is the mainstay of ulcer therapy and is particularly important for lesions in locations subject to trauma and infection, such as the perineum (picture 3). Local wound care reduces pain and helps to prevent secondary infection [97]. Commonly used therapies include topical antibiotics, barrier creams, and non-stick dressings [98]. Very gentle debridement of crusted wounds with saline soaks two to three times daily may also be helpful since crusting prevents re-epithelization and favors infection.
There are a few reports of successful use of topical timolol for the treatment of ulcerated hemangiomas [99-102]. In one retrospective analysis of 30 children with hemangiomas with focal to 3 cm ulcerations predominantly located in intertriginous areas, treatment with one drop per day of timolol 0.5% gel led to ulcer resolution after an average of 67 days [102]. (See 'Topical beta blockers' above.)
Topical metronidazole gel, often used in combination with topical mupirocin, has proved to be safe and efficacious for ulceration, particularly in intertriginous or moist areas such as the lip and perineum [97]. When clinically indicated, broad-spectrum oral antibiotics are also occasionally used.
Becaplermin, a synthetic form of platelet-derived growth factor, is approved by the US Food and Drug Administration for treatment of lower-extremity diabetic neuropathic ulcers. It has been reported to be effective as a second-line topical therapy in the treatment of ulcerated hemangiomas that are refractory to standard care [103,104]. Becaplermin prescribing information contains a boxed warning about the possible risk of death from cancer in patients who receive repeated treatment with becaplermin [105]. The studies that prompted the warning were performed in adult patients with diabetes. No cases of cancer have been reported in children who were treated with becaplermin for hemangioma ulceration.
Oral propranolol — We suggest oral propranolol in addition to meticulous wound care and appropriate analgesia for the treatment of ulcerated hemangiomas that may cause permanent disfigurement; interfere with daily life activities (eg, diaper changes, bathing, feeding, sleeping); or are unresponsive to wound care and pain and infection control. (See 'Propranolol' above.)
A beneficial effect of propranolol on ulcerated hemangiomas has been reported in several case series [106-109].
●In two studies, treatment with oral propranolol (2 to 2.5 mg/kg per day) was associated with a shorter time to pain control and healing (mean time to healing of 4.3 and 8.7 weeks compared with 22.4 weeks in a group of historical controls treated only with supportive measures) [106,107].
●In another study, 64 infants with ulcerated hemangiomas of the head and neck region were treated with oral propranolol 2 mg/kg per day in three divided doses or a combination of ibuprofen 10 mg/kg and paracetamol 16.2 mg/kg every eight hours for up to six months [110]. A complete or partial response was achieved in 24 of 28 patients in the propranolol group and in 12 of 24 patients in the ibuprofen/paracetamol group, with a mean time to healing of 18 and 28 days, respectively.
Analgesia — The pain associated with ulceration can be severe. Affected infants commonly suffer from sleep disturbance and increased irritability. Use of oral acetaminophen (with or without codeine) or a topical anesthetic agent (ie, lidocaine hydrochloride 2 to 5% ointment) may be warranted. To avoid the risk of lidocaine toxicity, parents should be instructed to apply only a pea-sized amount of lidocaine to the affected area no more than four times per day.
Eutectic mixture of local anesthetics (EMLA) should be avoided in infants less than three months of age because it contains prilocaine hydrochloride, which has been associated with infantile methemoglobinemia. Infants younger than three months have low levels of methemoglobin reductase. The risk of methemoglobinemia is increased when EMLA is used concomitantly with other methemoglobinemia-associated drugs (table 1). (See "Genetics and pathogenesis of methemoglobinemia", section on 'Infants and children'.)
Pulsed-dye laser — Pulsed-dye laser (PDL) 595 nm can be used as an adjunctive treatment for ulcerated hemangiomas that fail to heal after medical therapy and optimal wound care [1]. Treatment can be repeated at two- to four-week intervals. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Infantile hemangiomas'.)
Airway hemangiomas — Because of the small caliber of the infant airway, a growing airway hemangioma can lead to life-threatening airway obstruction. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Airway hemangiomas'.)
Systemic propranolol is generally the first line of therapy for children with symptomatic airway hemangiomas [39,111]. Laser ablation is an occasional second-line therapy [112]. Rarely, tracheotomy may be required.
In a multicenter study, 27 infants aged one to five months with airway hemangiomas were treated with oral propranolol 2 mg/kg per day for a median time of 15 months (range 7 to 34 months) [113]. Eleven children were treated with propranolol alone, whereas 16 received intralesional corticosteroid injection at the time of propranolol initiation. The symptoms of stridor generally resolved within a day of initiation of propranolol treatment. However, additional therapy, including systemic steroids, laser ablation, or surgical excision, was required in 16 children because of recurrence of respiratory symptoms.
High-output failure — Infants with significant hepatic or very large cutaneous hemangiomas may rarely develop high-output heart failure within the first several months of life. Treatment in such cases may include: systemic propranolol and/or glucocorticoids; vincristine or interferon in unresponsive, life-threatening cases; hepatic arterial embolization in selected hepatic cases; and/or treatment of heart failure (with fluid restriction, diuretics, and digoxin as indicated) [114,115].
PHACE syndrome — The presence of severe arterial anomalies may restrict the use of propranolol in some patients with PHACE syndrome (MIM 606519) [116]. In addition to large facial hemangiomas, patients with this disorder exhibit coarctation of the aorta and abnormalities of the cerebral and cervical vasculature and vessels of the aortic arch. It is known that a small percentage of patients with severe cerebral or cervical anomalies develop acute arterial ischemic stroke, most often during infancy or toddlerhood [117]. Thus, there is at least theoretical concern that propranolol-induced hypotension and reduced cerebrovascular perfusion in patients with already compromised cerebral vasculature could increase the risk of stroke in this population [116]. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'PHACE syndrome'.)
Consensus guidelines recommend that infants with PHACE syndrome be thoroughly evaluated with magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) of the head and neck and cardiac imaging to include the aortic arch before starting propranolol treatment [34]. MRA findings that confer the highest risk of stroke include severe, long-segment narrowing or nonvisualization of major head or neck arteries without adequate collateral/compensatory circulation, especially in the presence of concomitant cardiac and aortic arch anomalies [117].
The risks and benefits of propranolol treatment for patients with PHACE syndrome who have high-risk MRA features should be discussed in consultation with neurology and/or cardiology specialists [34]. If the potential benefits of propranolol treatment are deemed to outweigh the risks, propranolol should be given at the lowest possible dose, with slow upward dose titration and three-times-daily dosing [34]. This schedule is aimed at minimizing abrupt changes in systolic blood pressure, which is a known risk factor for stroke.
In a retrospective study, 32 children with PHACE syndrome were successfully treated with propranolol at the average dose of 1.8 mg/kg per day [118]. One patient experienced mild right-side hemiparesis, and two had soft tissue effects (eg, worsening of ulceration, acrocyanosis, nail dystrophy, small digital infarcts). Although no severe neurologic events were reported in this large case series, the possibility that propranolol augments the potential risk of stroke in this population cannot be ignored.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Hemangioma (The Basics)")
●The approach to the treatment and the choice of treatment modality for infantile hemangiomas should be individualized depending upon the size of the lesion(s), location, presence of complications, potential for scarring or disfigurement, the age of the patient, the rate of growth or involution at the time of evaluation, the potential risk(s) and benefits of treatment, the availability of the various modalities, and the experience of the treating clinician. (See 'General approach' above.)
●Treatment is usually required for complicated hemangiomas that may interfere with a vital structure or function and for lesions at increased risk of ulceration, scarring, and disfigurement. The goals of treatment include prevention or reversal of life- or function-threatening complications; prevention or minimization of disfigurement, bleeding, infection, and pain; and minimization of psychosocial distress for the patient and family. (See 'Indications for intervention and goals of treatment' above.)
●We suggest active nonintervention for uncomplicated hemangiomas that are not disfiguring (Grade 2C). Active nonintervention requires regular monitoring of the clinical course and attention to the psychosocial implications for the child and family. (See 'Active nonintervention' above.)
●We recommend oral propranolol as the first-line agent for the treatment of complicated hemangiomas with the potential to impair function or cause disfigurement (eg, periorbital hemangiomas) (Grade 1A). Treatment is started with 0.5 to 1 mg/kg per day and then gradually increased to the target dose of 2 mg/kg per day (algorithm 1). (See 'Propranolol' above and 'Administration' above.)
●Systemic glucocorticoids, vincristine, and interferon alpha are alternative agents for aggressive hemangiomas but are rarely needed since the advent of propranolol. (See 'Systemic corticosteroids' above and 'Other systemic therapies' above.)
●Children with periorbital hemangiomas should be evaluated by an ophthalmologist who is experienced in the treatment of hemangiomas. (See 'Periocular hemangiomas' above.)
●We suggest oral propranolol in addition to meticulous wound care and appropriate analgesia for the treatment of ulcerated hemangiomas that may cause permanent disfigurement, interfere with daily life activities, or do not respond to wound care measures (Grade 2C). (See 'Ulcerated hemangiomas' above.)
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text:
Today is Aaliyah's birthday. I actually forgot it, honestly. But it just happened coincidentally that I was browsing for this song just this very moment when I also read on my Facebook news feed about a friend's post regarding today's birthday of Aaliyah.
And for today's birthday of Aaliyah, I wanna share this music video of hers.

subset: commoncrawl


text:
It's time to make MORE donuts.
Clyde's Donuts (1120 W. Fullerton Avenue, Addison IL; 630-628-6555; clydesdonuts.com) has kicked off its new manufacturing space, along with a new logo and slogan, in a glaze of glory.
This Addison-based 4th-generation family-owned and -operated business of 96 years makes donuts and fritters, which are sold through private-label, retail, and contract customers. At a Ribbon Cutting Ceremony on February 19, Clyde's officially celebrated the launch of its new brand and facility expansion. The 4th production line and expanded freezer space bring the total facility area to 104,000 square feet. "The expansion was based on our success with our current customers," explains Kim Bickford, CEO. "We focus on Customer Intimacy - delivering above and beyond expectations and being customer-centric - that's what's spurred all of this growth, and our newly increased capabilities will help us ensure its continuation."
The added production capacity will accommodate up to a million donuts per day, according to Director of Operations Nero Patel; "That's a big breakfast!" he jokes. David Bennett, Senior Vice President of Sales and Marketing, adds that a newly set target of doubling Clyde's business within 5 years "is a lofty short-term goal, but it's manageable." Clyde's business partners include in-store bakeries in supermarkets, convenience stores, foodservice groups, distributors, and contract manufacturing customers. "One thing that we bring to the table is that we ONLY do donuts," Bennett notes; "we truly specialize."
The project was a true labor of love for the Clyde's team, and a true work of partnership between Clyde's and the Village of Addison. Mayor Rich Veenstra praises Clyde's commitment to the Village. "Clyde's has been a role model for businesses in Addison…. They saw the advantages of remaining in Addison, and we worked with them to facilitate the realization of their needs."
Perhaps one reason for the solidity of this company's culture is its Chairman, family patriarch Bill Bickford, who proudly proclaims his "pride in family and these generations of dedicated employees." Bill started working with his father-in-law at Clyde's when he was 20 years old, and bought the company in 1962. Clyde's boasts 3 generations of Bickfords still at the helm, from patriarch Bill, to brothers Kim and Kent, to grandson Josh (son of Kim); the workplace dynamic strengthens the family bond as well as the business.
Josh Bickford, who joined the family business in 2009 and leads Continuous Improvement programs, is enthusiastic that the new logo (a sprinkle-and-frosting decorated donut, bitten to resemble the letter C) and slogan "Smiles All Around" truly sum up the Clyde's experience. "People transfer the love of enjoying a donut to their kids. It's not trite - the thought of enjoying a donut evokes a feeling; a donut moment, if you will. The joy of donuts." Now, Josh and his wife are expecting their 2nd child, and focus is strongly on the rebranding and bringing the Clyde's variety of sweet success to new partners and customers, possibly with a 5th generation to someday join the team. Josh beams, "I'm so proud to be part of a family that is literally working together and constantly building."
Kent Bickford, brother of Kim and CFO of Clyde's Donuts, summed up the reason why this attitude is alive and well at Clyde's in his Welcome speech at the event: "The whole is greater than the sum of its parts: that's synergy." And that concept is robust at Clyde's, where in Kent's words, "employee dedication is everything; our employees are like family to us."
"In my lifetime," explains Bill, "I've seen this business grow from a tiny shop in Chicago's Lincoln Park to this large facility here. We've always done good business, we've always taken care of our employees, and we've always loved working with our current and new customers, because we're all like family."
That sentiment resonates throughout all 104,000 square feet of the facility, along with the sentiment that the Clyde's 'family' is all in this together and believes in the power of a donut.
Because, as Chairman and great-grandfather Bill Bickford neatly concludes, "Even after all this time, I still love donuts!"
About Clyde's Donuts:
Since its purchase by Herman Seekamp in 1920, Clyde's Donuts has excelled in serving fresh donuts and fritters to Chicagoland's restaurant and food service industry. Willard Bickford (Herman's son-in-law) purchased the company in 1962, thus commencing a course of growth that still continues today. Clyde's carries a complete line of Ready-to-Finish, Ready-to-Sell, and Ready-to-Serve donuts.
The entire Clyde's team is proud to say that the cornerstones of the family-owned and -managed company's success are employee commitment to quality, service, and value, as well as the exceptional loyalty of its customers.
Clyde's Donuts
1120 W. Fullerton Avenue, Addison IL 60101
Tel: (630) 628-6555
Email: email@example.com
Web: www.clydesdonuts.com
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Volume 204 of the series Topics in Current Chemistry pp 127-181
Thiocarbonyl Compounds as Specific Tools for Organic Synthesis
- Patrick MetznerAffiliated withLaboratoire de Chimie Moléculaire et Thio-organique (UMR CNRS # 6507), ISMRA - Université de Caen
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Thiocarbonyl compounds (thioamides, thioesters, thioketones...) react readily with a large variety of reagents (nucleophiles, electrophiles and radicals) due to their weak C=S bond and the aptitude of sulfur to stabilise an adjacent charge or radical centre. Thus, nucleophilic additions, deprotonation, and sigmatropic rearrangements are often more facile than in the oxygen series. Moreover, a number of specific reactions have been uncovered: thiophilic addition of nucleophiles, Michael addition of enethiolates, the Eschenmoser reaction, oxidation to sulfines, a large variety of [4+2] and [3+2] cycloaddition reactions with 1,3-dienes and 1,3-dipoles. Far from being purely exotic species, thiocarbonyl compounds are now efficient and specific tools and have indeed been used in multi-step synthetic schemes leading to various products of biological interest.
KeywordsThiocarbonyl compounds Thiophilic addition Cycloaddition reactions Enethiolisation Eschenmoser reaction Sigmatropic rearrangement
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- Title
- Thiocarbonyl Compounds as Specific Tools for Organic Synthesis
- Book Title
- Organosulfur Chemistry I
- Pages
- pp 127-181
- Copyright
- 1999
- 10.1007/3-540-48956-8_2
- Print ISBN
- 978-3-540-65787-3
- Online ISBN
- 978-3-540-48956-6
- Series Title
- Topics in Current Chemistry
- Series Volume
- 204
- Series ISSN
- 0340-1022
- Publisher
- Springer Berlin Heidelberg
- Copyright Holder
- Springer-Verlag Berlin Heidelberg
- Additional Links
- Topics
- Keywords
- Thiocarbonyl compounds
- Thiophilic addition
- Cycloaddition reactions
- Enethiolisation
- Eschenmoser reaction
- Sigmatropic rearrangement
- Industry Sectors
- eBook Packages
- Editors
- Editor Affiliations
- 11. Department of Chemistry, Loughborough University
- Authors
- Patrick Metzner (12)
- Author Affiliations
- 12. Laboratoire de Chimie Moléculaire et Thio-organique (UMR CNRS # 6507), ISMRA - Université de Caen, 6 Boulevard du Maréchal Juin, F-14050, Caen, France
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Detective James Wolf earned the nickname Lone Wolf from his inability to work with a partner. He's a hard cop who doesn't mind bending the rules to the breaking point to make a case, which is why Internal Affairs is digging in his backyard, looking for buried bones. People are starting to wonder which side of the law the Lone Wolf really hunts for. With his career hanging by a thread, he needs a major show of good faith to stay employed and out of prison. That's when he gets the call.
From the moment he arrives at the crime scene, Detective Wolf knows he's in over his head. He's a narcotics detective called in to consult on a homicide, but this is no ordinary homicide - a priest was butchered in his own church, the body left behind with a promise of more to follow.
The only lead is the killer's calling card: a black lotus flower. Detective Wolf now has the opportunity to wipe his service record clean, in exchange for tracking and stopping the Black Lotus before the next victim is claimed.
Accepting this assignment was Wolf's attempt to get Internal Affairs off his back. But when his hunt for the Black Lotus leads him to a cold case from his past, it becomes personal.
©2014 K'wan (P)2014 Blackstone Audio, Inc., and Buck 50 Productions, LLC
Audio books are growing. I have listened to books for months now, But I prefer my books in paperback/hardback format.
"Good book"
I finally got this book and finally listen to it lol. This book was good it didn't take me long to read I'm glad all of them got what was coming to them because I hate pedophiles . I was so glad nothing happened to Wolf. lol I liked that man but I was waiting on him and Kallalah to get together lol. But good read though. I liked this it's definitely a 5 star read.
"Eyes everywhere"
Was really interesting it, I got the feel of urban sci-fi instead of urban mystery b/c of the way The Black Lotus was potrayed.
"The lotus"
Do not have the written version; enjoy the way Cary Hite narrates.
the way of the plot was outline left you wishing for more; hence you listened longer.
Cary Hite's is one of the best performer because he makes every character distinguish and original.
The past; redemption
"it was okay"
a lot going on that was extra and didn't fit into the plot. I was disappointed.
Beware The Black Lotus!
For Justice Will Be Served In Blood, & In Blood Only...
It Is God's Will!
"Great character story"
I love this character and she needs to have another story based on her whole life and not just portion. and wolf needs to be flushed out more too.
"Cee's Thoughts"
Loved it!! Kwan is a magnificent writer. I encourage everyone to read his stories!! Yes!
"wish it was longer"
Good story. Would like to hear more. I like the characters but would like a longer version.
"On your toes"
The narrator has a dreamy voice, I love it. The narrative has you on the edge of your seat, speculating whose doing what and the motive. Some characters appear from other books, written by K'wan. Additionally trying to figure out what side of the law the detective is on. Although short, I enjoyed it, not sure it could have been longer. The details and the suspense have your mind mentally flipping back through, trying to figure out stuff.
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- Luxurious accommodations
- Two VIP tickets to the Nutcracker
- Ballerina cookies upon arrival
- In-room hot chocolate nightcap for two
- In-room breakfast for two the following morning
- Joffrey Ballet "Swag Bag," including a signed pointe shoe, commemorative program and signed photo
CHICAGO, Dec. 12, 2012 /PRNewswire/ -- For 25 years, Joffrey Ballet has enchanted the hearts of many with its annual performance of the Nutcracker. This year, experience the magic of this holiday tradition and stay at JW Marriott Chicago, an exquisite downtown Chicago luxury hotel. From Dec. 9 to 27, Joffrey Ballet will deliver an iconic performance of the Nutcracker at the Auditorium Theatre of Roosevelt University, 50 East Congress Parkway, just a half mile from the sophisticated hotel. As an added bonus, JW Marriott Chicago is offering a VIP Nutcracker Ballet Package beginning at $475 per night. Distinct among Chicago hotel deals, the Nutcracker Ballet Package includes:


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Protein digestion
I am consuming whey protein 1 scoop after workout but it seems that I am not able to digest it. It feels heavy in my stomach whole day and also my belly size has increased due to it. I am not lactose intolerant. i have been drinking milk daily without any problems since long time. Dietician in my gym told me that you may have problems in digesting protein. Please suggest.
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Hi..., Protein is primarily broken down by hydrochloric acid in the stomach and pancreatic protein enzymes in the upper small intestine,.... Failure to effectively digest protein in the upper gastrointestinal tract allows larger undigested proteins to pass into the bowel where it is often decomposed by bacterial putrification – a process that can lead to diarrhoea, cramps, flatulence, bloating and other digestive complaints... Consult Physician....
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Finally, the date has arrived for a memorable moment in the history of Telugu cinema. That's the three generations of actors from the same family sharing the screen. It has happened only once in Indian cinema until now and the feat was achieved by Kapoor khandhan – Prithviraj Kapoor, Raj Kapoor and Randhir Kapoor with the movie 'Kal Aaj Aur Kal' which released in 1971.
History is repeating after 42 years with Akkineni family making the unbelievable happen – ANR, Nagarjuna and Naga Chaitanya coming together for Manam which is being directed by Vikram (Ishq fame). The trio will start shooting their combination scenes from September 9th.
Speaking about the Akkineni multistarrer, ANR says finding a script for such a combination is an herculean task but Director Vikram managed to come up with a highly entertaining subject. He,however, turns down the request of his fans to appear in a duet keeping his age in mind.
Nagarjuna reveals that the script has been filled with so many light-hearted moments between the trio to make it a laugh riot. He went on to say Chaitu will be very nervous with the idea of sharing screen space with him and his grandfather for the first time.
Naga Chaitanya admits being excited and nervous at the same time. He, however, is confident of getting over that jitters after the first few days of their combination scenes.


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I flinched when I saw the flames. We were too late to stop the house from burning. But I could also see the demon, a dark whispy shadow curling around on the roof. And I wanted to kill it.
Dad jumped out of the car as soon as he put it in park, then popped open the trunk. Lifting up the false bottom when I reached the car, I yanked out my handgun and the bag of lead shavings we had collected for this demon. Dad grabbed his sawed-off shotgun and the large water bottle.
It is surprisingly easy to kill a pyro demon. You need plenty of water, and lead, both of which are easy to get. All you have to do is dump both the water and the lead on the demon at the same time, and it will burn out. Of course, since the demon was on top of a burning building, that made things a little more difficult.
But dad and I work really well together. Probably because we have been working together for so long. Dad trusts me enough to let me take risks, like taking the lead and water bottle up onto the roof while he covers me with the shotgun.
After dad gave me a leg up, I was on the roof in a few seconds. It was hot, but the flames hadn't reached me yet, so I was okay, for now at least. I squinted around until I caught sight of the demon, then scrambled after it.
With a practiced flick of the wrist I got the sack open, then tugged the water bottle's squirt top open. Then, before the demon had even seen me, I slathered it in lead and water until there was nothing left but a pile of mush.
"I got it!" I shouted to dad.
That's when I heard the screaming start.
Of course, there had to have been someone in the house, I should have thought of that sooner. I dropped quickly off the roof and kicked open the nearest front door. Smoke billowed out of the house, since this was the side that was actually on fire. After glancing at dad, who nodded encouragingly towards me, I ducked inside.
The smoke was so bad I couldn't see, so I had to rely on my hearing. Thankfully, I was pretty good at listening. I heard a child's whimpering over the sound of the crackling fire and I dove in that direction.
A little girl squeaked at me, but instinctively wrapped her arms around me when I picked her up and hurried back outside. I set her on the grass, where she coughed a few times before crying, then turned back to the house.
The entire left side, where the little girl had come from, was a blaze, and the right side had caught fire as well. As I watched, a young father came dashing out of the house, two young boys in his arms. He set them on the grass, then dashed back inside.
"No!" I shouted at the man, but it was too late. He was inside the house, and the next moment the door was blocked by flames. He had probably gone back inside for his wife, and now he was dead as well.
I heard the sound of sirens in the distance, and glanced at dad. He nodded at me.
"We need to get out of here," he said and started for the car. I turned to follow him, but the little girl caught my attention.
She had a mass of auburn red curls. My eyes widened, recognizing her, and I turned to look at the two boys, who were holding on to each other tightly. One looked to be about eight, while the other was probably closer to four, and they both had brown hair. The little one could have been the boy from my senses.


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14k White/Rose Gold Round Double Halo
Engagement Ring
This glamorous double halo engagement ring includes the round cut center stone. A pink gold surprise adorns the gallery.
Style #:
Center Diamond Size:
Diamond Total:
* Includes center stone.
More Details
Crown Type:
- Collection: Blush
- Style: Double Halo
- Stone Shape:Round
- Width: 8.90 mm
- Thickness: 7.40 mm
- Bandwidth: 1.70 mm
- Size: 6.50
Product weights and dimensions are approximate.
Due to the price fluctuation in gold & diamonds, we reserve the right to adjust prices accordingly without notice.


text: To get from Niscemi to Voghera by train you can catch one of the 4 trains that everyday travel between these two cities. The first train to Voghera leaves from Niscemi at 06:22 and the last train departs at 13:15. If you choose a local train the trip lasts on average 01:10 hours. For your trip from Niscemi to Voghera by train you can choose to leave from one of Niscemi main stations: Niscemi On Wanderio you can compare all schedules, fares and railway companies to Voghera and book the best itinerary starting from Niscemi.


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8370 Parkview Avenue NE, Otsego, MN 55330
About the Listing
Pristine 1 bed/2bath End Unit townhome with an open floor plan and lots of natural light. This home has an abundance of space with over 1, 620 finished sq ft and a 2 car garage. There is plenty of room to entertain whether on your deck or your patio which you can access through the lower level walkout .Lower level drop ceiling will be completed prior to closing at sellers expense. Great location w/easy highway access, restaurants, shopping and more!
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Property Details for 8370 Parkview Avenue NE, Otsego, MN 55330
Bedrooms: 1
Bathrooms: 1 Full | 1 Three-Qtr
Lot Size: 0.05 Acres
Lot Dimensions: Common
Year Built: 2001
Garage Dimensions: 2 car
Garage: Attached Garage, Driveway - Asphalt, Garage Door Opener
Style: (TH) Side x Side
Neighborhood: Stonegate Estates
Water: City Water/Connected
Sewer: City Sewer/Connected
Square Feet: 1642
Above Ground Sq Ft: 904
Below Ground Sq Ft: 738 (approx)
Room Information for 8370 Parkview Avenue NE, Otsego, MN 55330
Upper Floor
Living Room: 16x11
Dining Room: 13x10
Kitchen: 15x10
Bedroom 1: 13x11
Deck: 10x8
Lower Floor
Family Room: 25x23
Main Floor
Foyer: 8x7
Dining Room Description: Living/Dining Room
School Information for 8370 Parkview Avenue NE, Otsego, MN 55330
School District: Elk River
School District Phone: 763-241-3400
Interior Features for 8370 Parkview Avenue NE, Otsego, MN 55330
Air Cond: Central
Heating: Forced Air
Fireplaces: No
Basement: (738 sq Finished) Walkout, Full
Exterior Features for 8370 Parkview Avenue NE, Otsego, MN 55330
Lot Dimensions: Common
Roof: Asphalt Shingles
Zoning: Residential-Single
Financial Considerations for 8370 Parkview Avenue NE, Otsego, MN 55330
Tax Amount: $1,276
Taxes w/Assessments: $1,276
Tax/Property ID: 118077010060
Tax Year: 2016
Monthly Payment = $0
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The data relating to real estate for sale on this web site comes in part from the Broker Reciprocity Program of the Regional Multiple Listing Service of Minnesota, Inc. Real estate listings held by brokerage firms other than the owner of this website are marked with the Broker Reciprocity logo or the Broker Reciprocity thumbnail logo and detailed information about them includes the name of the listing brokers.


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£425,000 Offers over
Tantallon House is one of the 'landmark' houses within the popular commuter village of Muirhead and a locally admired 'Victorian' family home.
Set on a prominent corner site within the original part of Muirhead, Tantallon House has been transformed by then addition of a large rear extension and the imaginative development of its attic into a guest suite, on partial open plan to a substantial recreation room.
The renovation of this handsome, classically styled family home has been carried out with considerable care retaining the original and defining architectural features including: stained glass windows, ornate ceiling cornice plasterwork (with corbels and celling roses), picture rails, balustrades and patterned quarry tiled floors.
Providing impressive and versatile accommodation the property comprises: entrance porch, broad, welcoming reception hall, bay windowed lounge, sitting room, family room/study (used as a library), truly exceptional 28' x 19' (maximum) family sized dining kitchen with integral utility room, pantry and French doors to the rear garden and 13' x 12' shower room with Doulton suite completes the ground floor. The first floor offers a bay windowed master bedroom with cleverly installed en-suite shower room, 3 further double bedrooms and quality tiled family bathroom with rolled top bath. Considerable imagination has been used in adapting the attic floor into a recreation room and semi open plan guest suite with bedroom and 'state of the art' en-suite bathroom (incorporating a shower enclosure and WC compartment - with curved wall).
Tantallon House boasts an attached (dry lined) gymnasium - originally the garage of the property and a purpose built garden studio / recreation room with French doors and low voltage down lighting. Extensive double glazing. Gas fired central heating system.
The beautifully landscaped garden offers exceptional privacy and features split - level patios, garden pond with fountain, 'Victorian' lamp standard and is perfectly suited to the rigours of modern family life.
Located in the popular suburb of Muirhead, which lies just off the A80 Cumbernauld Road North of Glasgow, a sought after residential street, which has a delightful mix of house styles, from modern to traditional. It is within walking distance of the local shops which cater for day to day requirements with more extensive shopping and recreational amenities in nearby Lenzie, Kirkintilloch, Cumbernauld and Stepps. There is a local bus service which links the area to Cumbernauld and Glasgow and the railway stations at Lenzie. Gartcosh and Stepps have regular services into Glasgow Queen Street Station. Motorway network including the M73 and M80, give access superb access to the central belt. Early viewing is recommended to fully appreciate the size and quality of this lovely family home and to avoid disappointment
Exceptional, locally admired 'Victorian' villa is the commuters dream purchase.
EER Band E
Lounge 19'3" (5.87m) into bay window x 15'2" (4.62m).
Sitting room 13'3" x 13' (4.04m x 3.96m).
Family room / study 13'7" x 12'8" (4.14m x 3.86m).
Dining kitchen 28'10" (8.79m) x 19'2" (5.84m) (maximum).
Utility room 7'4" x 5'1" (2.24m x 1.55m).
Master bedroom 19'3" (5.87m) into bay x 13' (3.96m).
Ensuite shower room 11'8" x 4'2" (max) (3.56m x 1.27m (max)).
Bedroom 2 13'5" x 12'5" (4.1m x 3.78m).
Bedroom 3 13' x 12'6" (3.96m x 3.8m).
Bedroom 4 13'6" x 12'11" (4.11m x 3.94m).
Guest bedroom 15'2" (4.62m) x 13'10" (4.22m) (maximum).
Ensuite bathroom 13'1" (3.99m) x 7'9" (2.36m) (maximum).
Attic recreation room 18'8" x 16'10" (5.7m x 5.13m).
Family bathroom 8'7" x 7'8" (2.62m x 2.34m).
Shower room 13'6" x 12'3" (4.11m x 3.73m).
Gymnasium 18'6" x 10'7" (5.64m x 3.23m).
Garden studio / recreation room 16' x 11'10" (4.88m x 3.6m).
This house description is based upon information supplied by the owner, or on behalf of the owner. These property particulars are produced in good faith and do not constitute or form part of any contract. s1homes do not take any responsibility for the accuracy of the information contained in this document.
If a property value displays '0', don't worry it just means no properties have been sold in that area during that time.
Sold house price data is supplied to us by the Registers of Scotland, a government department responsible for compiling and maintaining property registers, every month. There can be a delay of up to 3 months from when a property is sold to being recorded with Registers of Scotland. We provide house price data for your information only, we do not accept any liability for any errors. If you have noticed any incorrect information, please contact Registers of Scotland.


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Chastity Belt (gift)
12,628pages onAdd New Page
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this wiki
A gift that always gives -50 approval, specific to Zevran. Afterwards, it becomes a belt of the same name restricted to him. It will automatically be equipped on Zevran, replacing any belt he is wearing.
Requires Feastday Pranks DLC.
- Sold by Bodahn Feddic for 0 .


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Winning Over The Lost
I leave her, crying. This isn't right. She just implied that Mind didn't have our best interests at heart.
She's a heretic. She's a heretic but everything she has said makes sense to me. Why do we all need to look the same? Why can't we suggest that Mind isn't perfect? Nothing is perfect...except humans because of the selective breeding programme.
Some of the things that we've been fed just sound so stupid.
I get all of my men, all of the men I trust in to the mess hall just before lights out.
"Guys, most of you heard that we found a girl today."
Whispers start up amongst all of the men. It had just been a rumour...but here was their commanding officer stating it as a fact.
"She's said some things, and it certainly helped me realise something. Most of us have been here for twenty years because...damn it, I'll say it...because we aren't 100% commited to Mind."
There are a few cries of objection but I choose to ignore them.
"I'm going to even dare say that you've been following me instead of Mind."
I check Sergeant Rayjak's face, he nods at me.
"I've kept you alive. We've kept you alive, not Mind."
I say, gesturing to Rayjak and Sabiru.
"A lot of young, innocent people have died for Mind. I personally think that we should have our own lives. What give The Purple Brigade the right to tell us what to do? Because they're stronger than us? I haven't seen any of them out here fighting The Horde!"
More of my men are nodding now, they're with me.
"I wouldn't force anyone to risk their lives for me when we get back. But for those of you who agree with me, here's my idea..."
A few of the troopers leave at this point, but the rest stay, hanging on my every word.
"We're going to smuggle this girl to Aurelius 5 and we are going to overthrow Mind!"
They cheer. Rayjak grins at me and Sabiru remains passive.
We can do this.


text:
Terry Kay, a member of the Georgia Writers Hall of Fame and recipient of the Governor's Award in the Humanities, is the author of 16 works of fiction, including the classic To Dance with the White Dog and The Book of Marie. Three of his novels have been produced as Hallmark Hall of Fame movies.
When Arthur Benjamin steps from a Greyhound bus in Savannah, GA, he is immediately robbed by an affable street magician named Hamby Cahill. It is Hamby's first act of thievery and the remorse of it so overwhelms him that he finds lodging for Arthur in The Castle, a warehouse supposedly owned by Melinda McFadden, an eccentric and fragile grande dame of imagined aristocracy who is known as Lady to the strange assembly of street people she has arbitrarily selected to be her Guests.
There, Arthur finds his family: an ex-con shoplifter, a disgruntled seamstress, a young artist suspected of being a hooker, and a former boxer known as Lightning. For Arthur, it is the company that will change his life, as he, in turn, will change the lives of everyone he encounters.
Yet, he does not know he will become entangled with political arrogance over a minor traffic mishap, or be targeted for brutality. He does not know he will encounter Wally Whitmire, proponent of the Destiny of the Dominoes, or that he will become an unqualified mayoral candidate put forth to serve as an irritant to the incumbent Harry Geiger. And he does not know he will be looked upon by the people of Savannah, fortunate and unfortunate, alike, as an icon, a beloved figure who wears a cape of invented royalty and distributes paper flowers made of cocktail napkins as gifts of comfort. Arthur knows only that he has found his place and his purpose.