text:
The potential role of vitamin D for prevention and treatment of tuberculosis and infectious diseases
Il ruolo potenziale della vitamina D nella prevenzione e terapia della tubercolosi e delle malattie infettive
Catia DiniI; Antonio BianchiII
IDirezione Generate per la Cooperazione alio Sviluppo, Ministero degli Affari Esteri, Rome, Italy
IIASL di Bergamo, Bergamo, Italy
INTRODUCTION: Vitamin D deficiency (VDD) is a common condition among several populations in the world. VDD is associated with higher incidence of immune system disorders and faster progression of some infectious diseases. Vitamin D is known to be of physiological importance, it is considered an essential micronutrient for the bone health and plays a beneficial role in the prevention and/or treatment of a number of chronic diseases. Vitamin D has a complex action on the immune system.
RESULTS: Evidence that vitamin D protects against tuberculosis has been supported by in vitro, epidemiological and some preliminary clinical studies. Vitamin D has a potential effect on HIV (human immunodeficiency virus) and plays a crucial role in the defence against respiratory infections.
CONCLUSIONS: Vitamin D supplementation could be a low-cost, practical method to protect groups of people with high incidence of those diseases. Public health education should stress the need for adequate dietary intake of vitamin D in those vulnerable groups.
Key words: VDD, Vitamin D deficiency, tuberculosis, HIV, respiratory infections.
INTRODUZIONE: La carenza di vitamina D e una condizione comune in numerosi gruppi di popolazione nel mondo. Essa risulta associata a un'elevata incidenza dei disturbi del sistema immunitario e a una piu veloce progressione di alcune malattie infettive. Oltre ad essere un micronutriente essenziale per la salute dell'apparato scheletrico, la vitamina D riveste un ruolo importante nei processi fisiologici e nella prevenzione e/o terapia di numerose patologie croniche. Essa svolge un'azione complessa sul sistema immunitario.
RISULTATI: La dimostrazione che la vitamina D protegge contro la tubercolosi e stata supportata da studi in vitro, epidemiologici e da alcuni dati clinici preliminari. La vitamina D ha un effetto potenziale sull'HIV (sindrome da immunodeficienza acquisita) e svolge un ruolo fondamentale nelle infezioni respiratorie.
CONCLUSIONI: La somministrazione di vitamina D pud essere un metodo pratico, a basso costo per proteggere gruppi specifici di popolazione con elevata incidenza delle suddette malattie. L'educazione sanitaria pubblica dovrebbe mettere in risalto la necessita di una adeguata assunzione di vitamina D in tutti i gruppi vulnerabili.
Parole chiave: carenza di vitamina D, tubercolosi, HIV, infezioni respiratorie.
In the pre-antibiotic era, the role of vitamin D in prevention of infectious diseases has been very important. The cod liver oil, one of the most important nutritional source of vitamin D, was used both for treatment of rickets and tuberculosis (TB). Moreover, research has stressed the important role of vitamin D for the immune system. Due to the polyvalent action of vitamin D for the human health, in recent times its deficit has been investigated and associated with a number of different diseases.
Micronutrients as potential adjunctive immunotherapy are a growing field of medical attention since scientific evidence of a specific antimycobacterial activity of vitamin D3 in macrophages has increased. HIV (human immunodeficiency virus) and TB co-epidemics represent a setback to global control of tuberculosis. Hypovitaminosis D has been identified as a main risk factor for the development of TB. Therefore, vitamin D supplementation may represent a new strategy for the TB prevention and for the shortening of TB treatment in the face of growing drug resistance.
Vitamin D: an historical perspective
The discovery of vitamin D began with the recognition of rickets as childhood bone disease by Francis Glisson in 1650. The association between rickets and a lack of sunlight exposure was reported by Sniadecki in 1822. By the mid-19th century, cod liver oil has been established as an effective treatment for rickets [1]. Mellanby emphasized the role of the vitamin D as the preventing agent of rickets in 1919 [2]; while the first demonstration of its anti-rachitic properties was given by Elmer McCollum in 1922 [3]. By the 1930s, the use of cod liver oil in the treatment and prevention of rickets became common place. The bridging of the knowledge that photosynthesized vitamin D and vitamin D in cod liver oil were similar was responsible for the eventual conquest of rickets. In the same way, the utilization of vitamin D for treatment of tuberculosis was common in the pre-antibiotic era [4]. In the mid-19th century, cod liver oil was reported by Williams to provide improvement to patients with pulmonary tuberculosis [5] and it was subsequently found to contain high quantities of vitamin D3. The isolation of vitamin D3 from cod liver oil in order to treat tuberculosis in the 1930s led to its widespread use in TB treatment and prevention, until the introduction of antibacterial chemotherapy in the 1950s.
Vitamin D: endocrine metabolism
Vitamin D is considered an essential micronutrient. It is well known for its important role, together with calcium, in bone mineralization. Vitamin D in human body is present in several forms: the most important are 1,25-hydroxyvitamin D, the circulating form, and 1,25- dihydroxyvitamin D, the active form. Vitamin D is produced in the skin through exposure to UV light (through the transformation of 7-dehydrocholesterol in vitamin D3 or cholecalciferol) or absorbed from few foods. Vitamin D can be ingested in the form of vitamin D3 or vitamin D2 (ergocalciferol). Vitamin D2 is derived from irradiation of the fungal steroid ergosterol. The vitamin D is processed by 25-hydroxylase present in the liver to produce 1,25-hydroxyvitamin D. Finally 25 hydroxyvitamin D is transformed by the enzyme 25hydroxyvitamin D-1-a-hydroxylase (CYP27B1) in 1,25-hydroxyvitamin D, its active form. An important target organ for generation of 1,25-hydroxyvitamin D is the kidney, where the process is regulated by calcium metabolism signaling.
Vitamin D role in the immune system and tuberculosis
Vitamin D, in its active form 1,25-hydroxyvitamin D, has a complex action on the immune system, by modulating and inhibiting its activity in different ways. In 2006, Liu and colleagues proved that Mycobacterium tubercolosis sensing by the Toll-like receptor 2/1 (TLR2/1) complex increases expression of vitamin D receptors (VDR) and CYP27B1 in monocytes [6]. The synthesis of 1,25-dihydroxyvitamin D promotes VDR-mediated transactivation of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tubercolosis.
Cathelicidins have a direct antimicrobial function. In addition to anti-bacterial effects including membrane disruption, they have antiviral effect in the inhibition of herpes simplex viruses, adenovirus and retrovirus [7]. A study showed that macrophages are most efficient in producing cathelicidin antimicrobial peptide LL-37 after infection with M. tuberculosis, suggesting that cathelicidin from macrophages may be an important participant in the innate immune response during early infection in humans [8]. Liu (2006) demonstrated that transcriptional regulation of cathelicidin can be mediated by activation of 1,25-dihydroxivitamin D. Stimulation of TLR receptors in macrophages by microbial products results in increased conversion from the inactive 25-hydroxyvitamin D to the active 1,25-hydroxyvitamin D. According to Adams and colleagues, a consequence of TLR activation is the production of defensin-2 and of cathelicidin: these two antimicrobical peptides are strongly up-regulated by 1,25-hydroxyvitamin D [9]. In fact, according to Liu (2006), serum from donors with insufficient levels of dihydrovitamin D supported a lower induction of cathelicidin in monocytes compared to serum of donors with sufficient vitamin D levels. A similar conclusion has been reported by the above study of Adams, using serum from patients with insufficient levels of vitamin D, before and after vitamin D supplementation. Those further experiments have confirmed earlier evidence: the 4 ng/ml concentrations of vitamin D metabolites have been able in a reproducible way to protect infected human macrophages and restrict mycobacterial growth in vitro [10].
The crucial role played by vitamin D in the immune response to M. tuberculosis consists, as well as the production of the LL-37, in promoting phagolysosome formation [11].
A research has documented that 1,25-dihydroxyvitamin D promotes autophagy in monocytes [12]. Autophagy and vitamin D3-mediated innate immunity have demonstrated to confer protection against infection with intracellular Mycobacterium tuberculosis. A study of Eun-Kyeong confirms the scientific findings that antimicrobial peptides play central roles in innate immunity to mycobacteria, including direct killing and indirect immune modulation. Of particular interest, human cathelicidin LL-37 has shown to be a key component linking vitamin D3-dependent immunity and autophagy [13]. The study wishes further researches into how cathelicidin regulates innate immune responses in order to facilitate the development of combinatorial treatments involving antimicrobial peptides, nutritional deficit correction and conventional chemotherapy. This could represent a breakthrough in therapies for TB, especially for multidrug-resistant TB, which shows resistance to conventional antibiotics.
On the other hand, vitamin D binds the vitamin D receptors on natural killer T (NKT) cells and CD8aa. Both cells have an important role in regulating citokine production and in protecting against the generation of autoimmunity [14]. Researches have demonstrated that 1,25- dihydroxyvitamin D is a potent modulator of the T-cell phenotype: it inhibits the T-helper (Th) 1 T cells associated with cellular immune response while conversely enhancing humoral Th2 cells response [15, 16]. A recent finding indicates that a balance between pro-(Thl) and anti (Th2) inflammatory responses is optimal for control of TB, thus suggesting that the role of 1,25-dihydroxyvitamin D3 may have a relevant importance [17].
An overview
It is now widely recognized that vitamin D deficiency (VDD) is one of the most common conditions in the world. It has been estimated that upward of 50% of both children and adults living in the United States, Canada, Mexico, Europe, Asia, New Zealand, and Australia have vitamin D deficiency [18].
A recent national survey in the United States demonstrated that the prevalence of vitamin D insufficiency doubled in the last ten years: more than 90% of pigmented populations (Blacks, Hispanics, and Asians) suffer from vitamin D insufficiency, as well as nearly three fourths of the white population [19].
The reason why both Hispanics and Blacks are at much higher risk for VDD is mainly related to their skin pigmentation that gives them a natural sun protection factor, thereby reducing by 50% to 90% skin's efficiency in producing vitamin D3. When black American men and women were exposed to simulated sunlight, they were unable to raise their blood levels of vitamin D3, whereas white adults who received the same amount of simulated sunlight raised their blood levels of vitamin D3 by almost 50 fold [20]. High prevalence of hypovitaminosis D among black Americans has been found mainly in women [21].
A clinical research that investigated vitamin D metabolism showed that people from India residing in southern United States have reductions in serum vitamin D and 25(OH)D and are at risk of developing VDD, rickets and osteolmacia [22].
People in poor countries often have low vitamin D levels. In addition, darkly pigmented skin reduces the amount of UV light available in the skin for production of vitamin D. A comparative study carried out in Ethiopia has demonstrated that both ordinary Ethiopians and full term pregnant Ethiopian women living in Addis Ababa have a significantly decreased vitamin D status compared with pregnant Norwegian women living in Oslo [23].
In the Indian sub-continent several studies assessed the vitamin D level in the population. A study conducted in Northern Pakistan found 89% of adult patients with low vitamin D level [24]. An investigation from India has drawn attention towards wide prevalence of VDD in all the country, in all age groups including newborns, children, pregnant women and adult males and females residing in rural and urban areas. In both areas, widely prevalent VDD is functionally relevant to skeletal health including osteomalacia and rickets [25]. In 2005 a very high prevalence of hypovitaminosis D was observed in a research carried out among pregnant women and their newborn in northern India [26]. An investigation in Mysore found that sixty-seven percent of women had vitamin D deficiency and that at ages 5 and 9.5 years, children born to vitamin D-deficient mothers had smaller arm-muscle area in comparison with children born to mothers without deficiency [27]. A parallel research in New Delhi assessed a very high prevalence of vitamin D deficiency in healthy term born infants at the age of 3 months and their mothers in winter as well as summer [28].
In the Middle East and other Arab countries, the hypovitaminosis D is very frequent in children and adults. A cross-sectional study observed high prevalence of VDD in apparently healthy children living in Jeddah [29]. For cultural and religious reasons, the dress style of women outdoors prevents exposure of skin to sunlight. A cross-sectional randomized study conducted in Saudi Arabia indicated that VDD among healthy Saudi women of 25-35 years was 30% and 55% in women of > 50 years [30]. In Iran high percentage of VDD was defined in a population study: in Teheran prevalence of severe, moderate and mild VDD was 9.5%, 57.6% and 14.2% respectively [31]. New lifestyles, with an increase in time spent in artificial environment (offices, houses, commercial centres), mainly in the hottest season, limit the physiological ability of human body to synthesize from precursor "active" form of vitamin D.
The prevalence of vitamin D deficiency increased significantly with age. Although vitamin D levels may differ by latitude and skin pigmentation worldwide, there is growing evidence that living in sunlit areas may not provide adequate amounts of vitamin D, especially in postmenopausal women and old people. A study in Brazil assesses that although severe vitamin D deficiency leading to rickets or osteomalacia is rare in the country, there is accumulating evidence of the frequent occurrence of subclinical VDD, especially in elderly people [32].
Hypovitaminosis D and main diseases
Much debate has taken place over the definition of vitamin D deficiency. Most agree that a 25(OH)D concentration < 50 nmol/L, or 20 ng/mL, is an indication of vitamin D deficiency, whereas a 25(OH)D concentration of 51-74 nmol/L, or 21-29 ng/mL, is considered to indicate insufficiency; concentrations > 30 ng/mL are considered to be sufficient [33]. VDD is associated with various chronic diseases: osteopathy, myopathy, infections, inflammatory disease, hypertension, and diabetes mellitus [34], and auto-immune diseases (systemic lupus erythematosus and rheumathoid arthritis) [35] and is a risk factor for developing cardiovascular disease [36].
Rickets, although rare, is still diagnosed in the United States. Infants who are recent immigrants or adopted from orphanages abroad are at risk for rickets [37]. Vitamin D deficiency rickets is persistent in Canada, particularly among children who reside in the north and among infants with darker skin who are breastfed without appropriate vitamin D intake [38]. Rickets is among the most frequent childhood disease in many developing countries. In the Indian subcontinent and Middle East rickets is directly caused by VDD [39]. Moreover, a study in India suggests that rickets is common in malnourished children [40]. Inadequate exposure to sunlight appears to be the main factor responsible for the high incidence of the disease. In addition, malnutrition may contribute to the development of rickets [41].
The VDD is an important factor in the development of osteoporosis. An international epidemiological investigation of 18 countries at various latitudes conducted in 2004 and 2005 found a prevalence of vitamin D inadequacy among women with osteoporosis [42] and a study carried out in Italy assessed a high prevalence of osteoporosis in postmenopausal women due mainly to VDD [43].
TB patients frequently have lower vitamin D levels than the general population. Scientific research is studying the effect of vitamin D on the course of the TB disease. A recent study in Spain indicated that a high proportions of contacts of TB patients had low serum 25(OH)D levels and suggested that sufficient 25(OH)D levels protect against tuberculin skin test (TST) conversion, therefore supporting the hypothesis that deficient vitamin D status is a TB risk factor [44].
One of the major causes for globally VDD is a lack of sun-induced vitamin D synthesis. A survey in Germany among immigrant children and adolescents with a Turkish or Arab-Islamic origin found a high prevalence of vitamin D deficiency [45]. VDD has clearly re-emerged as a problem also in the UK, especially in children, mostly from Asian or Black ethnic minority groups [46]. The observation that migrants have lower serum vitamin D than do their healthy matched controls have led authors to conclude that the fall in vitamin D levels associated with migration from sunshine-rich to sunshine-poor areas is the cause for consequent reduction in cellular immunity that may allow a previously quiescent tuberculous focus to break down [47].
Martineau in 2011 observed that VDD was highly prevalent among black African adults living in Cape Town and is associated with susceptibility to active TB in both the absence and the presence of HIV infection, the association being stronger in HIV-infected people. Moreover, he pointed out that seasonal variations in vitamin D status and TB incidence among black Africans in Cape Town are causally related and suggested that all African immigrants should have their vitamin D levels checked, in order to restore the vitamin D deficiency [48].
A cross sectional study was conducted among pulmonary tuberculosis (PTB) patients in Mwanza, Tanzania to identify the predictors of their vitamin D status. The authors deduced that serum 25(OH)D is a valid measure of vitamin D status during the acute phase response and that the lower concentrations in PTB+ patients may reflect increased utilization of vitamin D [49].
A study by Gibney confirms the strong association between VDD and Latent Tuberculosis Infection (LTBI) in African immigrants in Melbourne [50]. A further study, among sub-Saharan African immigrants attending the infectious diseases clinics in Melbourne, documents the frequency of latent or active TB infection and the relationship with vitamin D deficiency [51].
In the Indian sub-continent, TB has historically been a public health concern, due to a high prevalence and incidence in the general population. In a cohort follow-up study from Pakistan, low vitamin D levels were associated with progression to active TB disease in healthy household contacts. The findings suggested also the higher susceptibility of women to the infection, because of their low socioeconomic status, poor nutrition, traditional/cultural traits, and little exposure to sunlight [52]. In Southeast Asian countries, TB is also a major public health issue. A study among the Vietnamese population in Ho Chi Minh City suggests that low vitamin D status is an antecedent risk factor for TB [53].
A review of several observational studies (UK, Indonesia, Kenya, Thailand, Hong Kong, India) found that patients with TB have, on average, lower serum levels of vitamin D than healthy controls matched on sex, age, ethnicity, diet and geographical location. Worries about VDD and the risk of TB may therefore not be limited to Arab countries, Afro-Asian indigenous and migrant communities, as half of people in Europe aged more than 60 years are vitamin D deficient and concerns have been expressed in the UK about increasing malnutrition in the elderly [54].
HIV represents a severe threat to the worldwide health, through population mobility. The VDD is particularly important in chronic illnesses, like HIV, both because the epidemiology of the disease coincides with the populations at higher risk of vitamin D deficiency and for the negative impact of protease inhibitors on vitamin D metabolism [55].
There is growing recognition of an association between VDD and the pathogenesis and course of HIV disease. According to a study, VDD was found frequent in HIV-infected persons of several countries of north, central, south Europe and Israel and was independently associated with a higher risk of mortality and HIV outcomes [56].
VDD has been demonstrated to be more frequent in HIV-positive patients than in healthy age and sex matched controls [57]. Insufficient levels of vitamin D may be one of several other risk factors contributing to the progression of HIV disease. Some crosssectional studies have indicated positive correlations between 1,25(OH)2D and CD4+ cell counts [58].
According to Spector, VDD is present in 25% to 75% of infected persons and has been associated with more rapid disease progression. In the meantime, infants born to HIV-infected women with vitamin D deficiency are at increased risk of infection and have decreased survival [59]. A study has indicated an association between low vitamin D levels and motherto-child transmission (MTCT) of HIV in developing countries. In a research in HIV-infected Tanzanian women, it was observed an increased risk of being HIV infected or of dying at birth for children born to women with a low vitamin D level at baseline. A low maternal vitamin D level was also associated with HIV transmission via breast-feeding and with higher infant mortality during follow-up [60].
In a further survey in the same cohort, low vitamin D levels at baseline were significantly associated with increased risk of HIV disease progression, severe anemia, and hypochromic microcytosis [61].
The above researches provide initial support for a potentially beneficial effect of adequate vitamin D status on HIV disease and related outcomes. Their results were consistent with one study which has found a correlation between higher vitamin D levels and increased survival times of HIV-infected patients [62].
Moreover HIV is correlated with the risk of tuberculosis co-infection. The TB is spreading quickly in developing countries, in sub-Saharan Africa and South Asia, and low-cost public health interventions for its prophylaxis are urgently needed. To restore the vitamin D level in the blood may prove to be an effective adjuvant treatment regimen for TB patients [63].
Vitamin D has complex effects on pulmonary cell biology and immunity with impact on inflammation, host defence, wound healing, repair, and other processes. First of all the epitelial cells of lungs express high level of CYP27B1, supporting conversion of vitamin D in its active form. Those cells treated with supplement of vitamin D increase the production of cathelicidin [64]. Studies have established a possible link between vitamin D and respiratory infections by examining VDR polymorphisms. Single polymorphism in VDR has been associated with severe outcomes in respiratory syncytial virus and lower respiratory tract infections [65]. Findings provide preliminary evidence of associations of VDR polymorphisms with the risk of acute lower respiratory infections (ALRI), predominantly viral bronchiolitis, in young children, consistent with a potential role of vitamin D in the immune response to respiratory tract infection [66].
Epidemiological and experimental researches highlight that low levels of serum vitamin D is associated with impaired pulmonary function and it is potentially involved in a number of lung diseases [67]. Moreover, a case-control study in Ethiopia determined the role of VDD as predisposing factor for pneumonia in children aged under 5 years [68].
Vitamin D deficiency increases patients' vulnerability to viral respiratory infections [69] and it is also involved in the pathophisiology of chronic rhinitis and rhinosinusitis [70].
Vitamin D appears capable of inhibiting pulmonary inflammatory responses while enhancing innate defence mechanisms against respiratory pathogens [71]. A study suggested higher vitamin D concentrations as a protective "seasonal stimulus" against influenza and other aspects of respiratory health [72].
An Indian clinical trial on 27 children treated for six weeks with a supplement of vitamin D orally has shown reduction in respiratory infections [73], while a British study on 1740 elderly patients, treated with 800 IU for two years, showed no significant reduction in respiratory infections [74]. The effect of vitamin D supplementation on incidence of respiratory infections seems relevant only when it is associated with a vitamin D deficiency, a relatively common situation in many developing countries. The findings have been confirmed by a Finnish research which found an association between 1,25(OH)2D concentration of less 16 ng/ml and an increase incidence of respiratory acute infections [75] and by a two-months study in Bangladesh which showed a significant correlation between lower levels of 25(OH)D (11,7 ng/ml against 15,7 ng/ml of control group) and increased number of respiratory infections [76].
Vitamin D has been attributed a significant role in host immune defence against M. tuberculosis as observational studies have found evidence of an association with VDD and active tuberculosis.
Clinical evidence using vitamin D in TB treatment was reported in several studies. The addition of vitamin D in the therapy of moderately advanced PTB had been proven to show a significant difference in sputum conversion compared with placebo. In a research carried out in Jakarta, the group treated with vitamin D had higher sputum conversion and radiological improvement (100%) as compared to the placebo group (76.7%) [77]. A black American woman with hypovitaminosis D and refractory drug-susceptible pulmonary TB was treated with antituberculous therapy and the correction of vitamin D deficiency. The patient demonstrated a significant radiographic improvement with negative sputum cultures at 13-month of total therapy [78].
In an Egyptian study vitamin D was administered to children with tuberculosis, showing that clinical improvement was more evident in patients taking vitamin D as compared to those who received treatment alone. The study concluded that vitamin D therapy may be very effective in addition to antituberculous drugs in the treatment of TB children [79].
Vitamin D has been suggested as prophylaxis in TB household contacts, being a low-cost intervention that is also easy to administer in resource-poor settings [80]. A research has demonstrated that a single oral dose of vitamin D enhanced tuberculosis contacts' antimycobacterial immunity in vitro. The finding that a single oral dose of 2.5 mg vitamin D corrects profound vitamin D deficiency for at least 6 weeks, without causing hypercalcemia, underlines the potential use of this formulation as a safe, effective, and low-cost public health intervention [81].
The administration of a single oral dose of 50 000-150 000 IU of vitamin D early in winter may be a convenient way to maintain 25(OH)D levels within the desirable range in children [82]. Children affected by VDD are likely to have suboptimal bioavailability of vitamin D, which might hamper their achievement of an adequate peak bone mass. Efforts to maintain an optimal supply of both vitamin D and calcium throughout the year seem warranted in order to facilitate bone accumulation and prevent osteoporosis later in life [83].
In veiled Arab women, vitamin D deficiency is the result of a combination of limitations in sunlight exposure and a low oral intake of vitamin D. Although exposure to sunlight is a key way to ensure enough levels of vitamin D in the body, however, addressing dietary intake of vitamin D to people who may avoid sunlight exposure for cultural believes seems a more successful way.
A research suggests that daily oral intake of vitamin D in sunlight deprived individuals should exceed 600 IU; probably it should be 1000 IU/day to secure a normal level of 25-hydroxyvitamin D. This finding was confirmed in a cross-sectional study among randomly selected Moslem women of Arab origin living in Denmark. Although the daily oral intake of vitamin D among those veiled women was very high, (approximately 600 IU), they were still vitamin D-deficient [84].
An adequate supply of vitamin D may be important in HIV-infected individuals with their additional risk factors for osteopenia, neoplasias or cardiovascular disease [85]. Moreover vitamin D supplementation reduces the incidence of rheumatoid arthritis, insuline-dependent diabetes mellitus, multiple sclerosis [86, 87] and prevents the risk of osteoporotic fractures in older persons [88, 89].
The oral administration of vitamin D should consider an important fact: storage of vitamin D is difficult, particularly considering the risk of oxidative inactivation of the micronutrient. A key point for an effective supplementation should be the use of oral monodose, packed with commonly used nitrogen technology, to avoid any risk of oxidative stress. The cheap cost of vitamin D (60 USD/kg) makes it an affordable technology for developing countries.
The overlapping of HIV and TB epidemics creates an health care crisis. The potential ability of vitamin D to fight TB, a leading cause of death in HIV-infected patients, mainly in sub-Saharan Africa, could lead to decrease in mortality or slower the disease progression. Investing in TB control in poor settings can be a cost-effective approach.
The connection among vitamin D, infections and immune function in the pediatric population indicates a possible role for vitamin D supplementation [90]. A study tested the association between vitamin D deficiency rickets and protein-energy malnutrition (PEM) in Ethiopian children and suggested that programmes targeting vitamin D deficiency rickets should give emphasis to children with PEM [91].
The relationship between rickets and maternal vitamin D deficiency has important implications for a comprehensive prevention strategy of vitamin D deficiency in women and children in the poorest settings of developing countries [92]. Moreover, the potential health consequences of VDD are very crucial in Africa and Asia where the infectious disease burden is high and malnutrition and famine are spreading in many populations, lowering their immune system [93]. Therefore programmes should be planned in order to provide vitamin D mainly to pregnant women and children.
In the western countries, more attention should be paid to the nutritional and vitamin D needs of older people and of all high risk groups (immigrants, HIVsubjects, TB patients) who are prone to hypovitaminosis D.
Public health education should stress the need for adequate dietary intake of vitamin D in vulnerable groups of people all over the world.
The ideas expressed in this paper do not necessarily reflect any official view of the Italian Ministry of Foreign Affairs.
Conflict of interest statement
There are no potential conflicts of interest or any financial or personal relationships with other people or organizations that could inappropriately bias conduct and findings of this study.
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23. Feleke Y, Abdulkadir J, Mshana R, Mekbib T, Brunvand L, Berg JP, Falch JA. Low levels of serum calcidiol in an African population compared to a North European population. Eur J Endrocrinol 1999;141:358-60. http://dx.doi.org/10.1530/eje.0.1410358
24. Mufti MA, Malhi UR, Zubair A, Badar I, Mufti M. Vitamin D levels in Adults in Northern Pakistan. RMJ 2012;37(1).
25. Goswami R, Mishra SK, Kochupillai N. Prevalence & potential significance of vitamin D deficiency in Asian Indians. Indian J Med Res 2008;127:229-38.
26. Sachan A, Gupta R, Das V, Agarwal A, Awasthi PK, Bhatia V. High Prevalence of vitamin D deficiency among pregnant women and their newborns in northern India. Am J Clin Nutr 2005;81:1060-4.
27. Krishnaveni GV, Veena SR, Winder NR, Hill JC, Noonan K, Boucher BJ, Karat SC, Fall CHD. Maternal vitamin D status during pregnancy and body composition and cardiovascular risk markers in Indian children: the Mysore Parthenon Study. Am J Clin Nutr 2011;93:628-35. http://dx.doi.org/10.3945/ajcn.110.003921
28. Jain V, Gupta N, Kalaivani M, Jain A, Sinha A, Agarwal R. Vitamin D deficiency in healthy breastfed term infants at 3 months & their mothers in India: Seasonal variation & determinants. Indian. J Med Res 2011;133(3):267-3.
29. Mansour MMHK, Alhadidi KM. Vitamin D deficiency in children living in Jeddah, Saudi Arabia. Indian J Endocrinol Metab 2012;16(2):263-9. http://dx.doi.org/10.4103/2230-8210.93746
30. Al-Turki H, Sadat-Ali M, Al-Elq AH, Al-Mulhim FA, Al-Ali AK. 25-Hydoxyvitamin D levels among healthy Saudi Arabian women. Saudi Med J 2008;29(12):1765-8.
31. Hashemipour S, Larijani B, Adibi H, Javadi E, Sedaghat M, Pajouhi M, Soltani A, Shafaei AR, Hamidi Z, Khalili Fard AR, Hossein-Nezhad A, Booya F. Vitamin D deficiency and causative factors in the population of Tehran. BMC Public Health 2004;4:38. http://dx.doi.org/10.1186/1471-2458-4-38
32. Bandeira F, Griz L, Dreyer P, Eufrazino C, Bandeira C, Freese E. Vitamin D Deficiency: A Global Perspective. Arq Bras Endocrinol Metab 2006;640-6. http://dx.doi.org/10.1590/S0004-27302006000400009
33. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 2008; 87(Suppl.):1080S-6S.
34. Thacher TD, Clarcke BL. Vitamin D Insufficiency. Mayo Clin Proc 2011;86(1):50-60. http://dx.doi.org/10.4065/mcp.2010.0567
35. Diniz Lopes Marques C; Tavares Dantas A; Sotero Fragoso T; Branco Pinto Duarte AL. The importance of vitamin D levels in autoimmune diseases. Bras J Rheumatol 2010;50(1):67-80.
36. Wang T, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D'Agostino RB, Wolf M,Vasan RS. Vitamin deficiency and risk of cardiovascular disease. Circulation 2008;117:503-11. http://dx.doi.org/10.1161/CIRCULATIONAHA.107.706127
37. Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: A historical perspective. Pediatrics 2003;112;e132. http://dx.doi.org/10.1542/peds.112.2.e132
38. Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D deficiency rickets among children in Canada. CMAJ 2007; 177(2):161-6. http://dx.doi.org/10.1503/cmaj.061377
39. Pettifor JM. Vitamin D &/OR calcium deficiency rickets in infants & children: a global perspective. Indian J Med Res 2008;127:245-9.
40. Raghuramulu N, Reddy V. Serum 25-hydroxy-vitamin D levels in malnourished children with rickets. Arch Dis Child 1980;55:285-7. http://dx.doi.org/10.1136/adc.55.4.285
41. Raghuramulu N, Reddy V. Studies on vitamin D metabolism in malnourished children. B J Nutr 1982;47:231-4. http://dx.doi.org/10.1079/BJN19820030
42. Lips P, Hosking D, Lippuner K, Norquist JM, Wehren L, Maalouf G, Ragi-Eis S, Chandler J. The prevalence of vitamin D inadequacy amongst women with osteoporosis: an in>ternational epidemiological investigation. J Intern Med 2006;260:245-54. http://dx.doi.org/10.1111/j.1365-2796.2006.01685.x
43. Adami S, Giannini S, Bianchi G, Sinigaglia L, Di Munno O, Fiore CE, Minisola S, Rossini M. Vitamina D Status and response to treatment in postmenopausal osteoporosis. Osteoporos Int 2009;20(2):239-44.
44. Arnedo-Pena1 A, Juan-Cerdán JV, Romeu-Garcia1 A, Garcia-Ferrer D, Holguín-Gómez R, Iborra-Millet J, Herrero-Carot C, Sanchis Piñana MJ, Bellido-Blasco J, Ferrero-Vega JA, Safont Adsuara1 L, Silvestre Silvestre E, Meseguer Ferrer N, Rodrigo Bartual V. Latent tuberculosis infection, tuberculin skin test and vitamin D status in contacts of tuberculosis patients: a cross-sectional and case-control study. Inf Dis 2011;11:349. http://dx.doi.org/10.1186/1471-2334-11-349
45. Hintzpeter B, Scheidt-Nave C, Mueller MJ, Schenk L, Mensink GBM. Higher prevalence of vitamin D deficiency is associated with immigrant background among children and adolescents in Germany. J Nutr 2007;1482-90.
46. Ladhani S, Srinivasan L, Buchanan C, Allgrove J. Presentation of vitamin D deficiency. arch Dis Child 2004;89:781-4. http://dx.doi.org/10.1136/adc.2003.031385
47. Davies PDO, Brown RC, Woodhead SJ. Serum concentrations of vitamin D metabolites in untreated tuberculosis. Thorax 1985;40:187-90. http://dx.doi.org/10.1136/thx.40.3.187
48. Martineau AR, Nhamoyebonde S, Oni T, Rangaka MX, Marais S, Bangani N, Tsekela R, Bashe L, de Azevedo V, Caldwell J, Venton TR, Wilkinson RJ. Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa. Barry R. Bloom 2011. http://dx.doi.org/10.1073/pnas.1111825108
49. Friis H, Range N, Pedersen ML, Mølgaard C, Changalucha J, Krarup H, Magnussen P, Søborg C, Andersen AB. Hypovitaminosis D is common among pulmonary tuberculosis patients in Tanzania but is not explained by the acute phase response. J Nutr 2008;138:2474-80. http://dx.doi.org/10.3945/jn.108.094979
50. Gibney KB, MacGregor L, Leder K, Torresi J, Marshall C, Ebeling PR, Biggs B. Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from Sub-Saharan Africa. CID 2008;46:443-6. http://dx.doi.org/10.1086/525268
51. Gibney KB, Mihrshahi S, Torresi J, Marshall C, Leder K, Biggs B. The profile of health problems in African immigrants attending an infectious disease unit in Melbourne, Australia. am J Trop Med Hyg 2009;80(5):805-11.
52. Talat N, Perry S, Parsonnet J, Dawood G, Hussain R. Vitamin D Deficiency and Tuberculosis Progression. Emerg Infec Dis 2010;16(5):853-5. http://dx.doi.org/10.3201/eid1605.091693
53. Ho-Pham LT, Nguyen ND, Nguyen TT, Nguyen DH, Bui PK, Nguyen VN, Nguyen TV. Association between vitamin D insufficiency and tuberculosis in a Vietnamese population. BMC Infectious Diseases 2010;10:306. http://dx.doi.org/10.1186/1471-2334-10-306
54. Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 2008;37:113-9. http://dx.doi.org/10.1093/ije/dym247
55. Cozzolino M, Vidal M, Arcidiacono MV, Tebas P, Yarashesky KE, Dusso AS. HIV- protease inhibitors impair vitamin D bioactivation to 1,25 dihydroxyvitamin D. AIDS 2003;17:513-20. http://dx.doi.org/10.1097/00002030-200303070-00006
56. Viard J, Souberbielleb J, Kirkc O, Reekied J, Knysze B, Lossof M, Gatellg J, Pedersenh C, Bogneri JR, Lundgrenc JD, Mocroftd A. Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study. AIDS 2011;25:1305-15. http://dx.doi.org/10.1097/QAD.0b013e328347f6f7
57. Vescini F. Vitamin D deficiency in HIV-positive patients. HAART and correlated pathologies. 2010;7:7-11.
58. Villamor E. A potential role for vitamin D on HIV infection? Nutr Rev 2006;64:226-33. http://dx.doi.org/10.1111/j.1753-4887.2006.tb00205.x
59. Spector SA. Vitamin D and HIV: letting the sun shine in. Top antivir Med 2011;19(1):6-10.
60. Mehta S, Hunter DJ, Mugusi FM, Spiegelman D, Manji KM, Giovannucci EL, Hertzmark E, Msamanga GI, Fawzi WW. Perinatal outcomes, including mother-tochild transmission of HIV, and child mortality and their association with maternal vitamin D status in Tanzania. J Infect Dis 2009;200:1022-30. http://dx.doi.org/10.1086/605699
61. Mehta S, Giovannucci E, Mugusi FM, Spiegelman D, Aboud S, Hertzmark E, Msamanga GI, Hunter D, Fawzi WW. Vitamin D status of HIV-infected women and its association with HIV disease progression, Anemia, and Mortality. Plus one 2010;5:1-7. http://dx.doi.org/10.1371/journal.pone.0008770
62. Haug C, Mueller F, Aukrust P, Froland SS. Subnormal serum concentration of 1,25-vitamin D in human immunodeficiency virus infection: correlation with degree of immune deficiency and survival. J Infect Dis 1994;169:889-93. http://dx.doi.org/10.1093/infdis/169.4.889
63. Adams JS, Liu PT, Chun R, Modlin RL, Hewison M. Vitamin D in defense of the human immune response. Ann NY Acad Sci 2007;1117:94-105. http://dx.doi.org/10.1196/annals.1402.036
64. Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW. Respiratory epithelial cells convert inactive vitamin D in its active form: potential effects on host defense. J Immunol 2008;11:965-74.
65. Beard JA, Bearden A, Striker R. Vitamin D and the antiviral state. J Clin Virol 2011;50:194-200. http://dx.doi.org/10.1016/j.jcv.2010.12.006
66. Roth DE, Jones AD, Prosser C, Robinson JL, Vohra S. Vitamin D receptor polymorphism and the risk of acute lower respiratory tract infection in early childhood. J Infect Dis 2008;197:676-80. http://dx.doi.org/10.1086/527488
67. Herr C, Greulich T, Koczulla RA, Meyer S, Zakharkina T, Branscheidt M, Eschmann R, Bals R. The role of vitamin D in pulmonary disease: COPD, asthma, infection and cancer. Respir Res 2011;12:31. http://dx.doi.org/10.1186/1465-9921-12-31
68. Muhe L, Lulsegd S, Mason EK, Somones EAF. Case control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. The Lancet 1997;349:1801-4. http://dx.doi.org/10.1016/S0140-6736(96)12098-5
69. Cannel J, Vieth R, Umhau JC, Holik MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Review article: epidemic influenza and vitamin D. Epidemiol Infect 2006;134:129-40. http://dx.doi.org/10.1017/S0950268806007175
70. Abuzeid WM, Akbar NA, Zacharek MA. Vitamin D and Crhronic Rhinitis. Curr Opin Allergy Clin Immunol 2012;12(1): 13-7. http://dx.doi.org/10.1097/ACI.0b013e32834eccdb
71. Hughes DA, Norton R. Vitamin D and respiratory health. Clin Exp Immunol 2009;158:205. http://dx.doi.org/10.1111/j.1365-2249.2009.04001.x
72. Berry DJ, Hesketh K, Power C, Hypponen E. Vitamin D status has a linear association with seasonal infections and lung function in British adults. Brit J Nutr 2011;106:1433-40. http://dx.doi.org/10.1017/S0007114511001991
73. Rehman PK. Subclinical rickets and recurrent infections. J Trop Pedatr 1995;40:58. http://dx.doi.org/10.1093/tropej/40.158
74. Avenel A, Cook JA, MacLennan GS, Macpherson CG. Vitamin D supplementation to prevent infections: a substudy of a randomised placebo-controlled trial in older people. Age Ageing 2007;36:574-7. http://dx.doi.org/10.1093/ageing/afm091
75. Laaksi I, Ruohola JP, Tuohimma P, Auvian A, Haatja R, Pihlajamäki H, Ylikomi T. An association of serum vitamin D concentrations < 40 nmol/l with acute respiratory tract infection in young Finnish men. am J Clin Nutr 2007;86:714-7.
76. Roth DE, Shah R, Black RE, Baqui AH. Vitamin D status and acute lower respiratory infections in early childhood in Sylhet, Bangladesh. acta Paediatr 2010;99:389-93. http://dx.doi.org/10.1111/j.1651-2227.2009.01594.x
77. Nursyam EW, Amin Z, Rumende CM. The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. acta Med Indones 2006;38:3-5.
78. Yamshchikov AV, Oladele A, Leonard MKJ, Blumberg HM, Ziegler TR, Tangpricha V. Vitamin D as Adjunctive Therapy in Refractory Pulmonary Tuberculosis: A Case Report. South Med J 2009;102(6):649-52. http://dx.doi.org/10.1097/SMJ.0b013e3181a5d37e
79. Morcos MM, Gabr AA, Samuel S, Kamel M, el Baz M, el Beshry M, Michail RR. Vitamin D administration to tuberculous children and its value. Boll Chim Farm 1998;137(5):157-64.
80. Wejse C, Olesen R, Rabna P, Kaestel P, Gustafson P, Aaby P, Andersen PL, Glerup H, Sodemann M. Serum 25-hydroxyvitamin D in a West African population of tuberculosis patients and unmatched healthy controls1-3. Am J Clin Nutr 2007;86:1376-83.
81. Martineau AR, Wilkinson RJ, Wilkinson KA, Newton SM, Kampmann B, Hall BM, Packe GE, Davidson RN, Sandra M, Eldridge SM, Maunsell ZJ, Rainbow SJ, Berry JL, Griffiths CJ. A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med 2007;176:208-13. http://dx.doi.org/10.1164/rccm.200701-007OC
82. Oliveri B, Cassinelli H, Mautalen C, Ayala M. Vitamin D prophylaxis in children with a single dose of 150 000 IU of vitamin D. Eur J Clin Nutr 1996;50(12):807-10.
83. Docio S, Riancho JA, Perez A, Olmos JM, Amado JA,Gonzalez -Macias J. Seasonal Deficiency of Vitamin D in Children: A potential target for osteoporosis-preventing strategies? J Bone Miner Res 1998;13:544-8. http://dx.doi.org/10.1359/jbmr.19184.108.40.2064
84. Glerup H, Mikkelsen K, Poulsen L, Hass E, Overbeck S, Thomsen J, Charles P, Eriksen EF. Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited. JIM 2000;247:260-8. http://dx.doi.org/10.1046/j.1365-2796.2000.00595.x
85. Mueller NJ, Fux CA, Ledergerber B, Elzi L, Schmid P, Dang T, Magenta L. High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. AIDS 2010;24:1127-34. http://dx.doi.org/10.1097/QAD.0b013e328337b161
86. Cantorna MT, Mahon BD. Mounting Evidence for Vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med 2004;229:1136-42.
87. Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 2007;66:1137-42. http://dx.doi.org/10.1136/ard.2007.069831
88. Bishoff-Ferrari HA, Willet WC, Wong JB, Giovannucci E, Ditrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation. JAMA 2005;293:2257-64. http://dx.doi.org/10.1001/jama.293.18.2257
89. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326:1-6. http://dx.doi.org/10.1136/bmj.326.7387.469
90. Walker VP, Modlin RL. The vitamin D connection to pediatric infections and immune function. Pediatr Res 2008;65:106R-13R. http://dx.doi.org/10.1203/PDR.0b013e31819dba91
91. Lulseged S, Fitwi G. Vitamin D deficiency rickets: socio-demographic and clinical risk factors in children seen at a referral hospital in Addis Ababa. East afr Med J 1999;76(8):457-61.
92. Dawodu A, Wagner CL. Mother-child vitamin D deficiency: an international perspective. Arch Dis Child 2007;92:737-40. http://dx.doi.org/10.1136/adc.2007.122689
93. Prentice A, Schoenmakers I, Jones KS, Jarjou LMA, Goldberg GR. Vitamin D deficiency and its health consequences in Africa. Clinic Rev Bone Miner Metab 2009;7:94-106. http://dx.doi.org/10.1007/s12018-009-9038-6
▲ Address for correspondence:
Catia Dini
Direzione Generale per la Cooperazione allo Sviluppo, Ministero degli Affari Esteri
Piazzale della Farnesina 1, 00135 Rome, Italy
E-mail: email@example.com
Received on 14 May 2012.
Accepted on 23 July 2012.


text:
You are here: Root > By Topic > Web DevelopmentView the dependency graph for this library
Portable library, accepts URI strings in accordance with the latest RFC3986 (including userinfo).
|Web site
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|2.0.007 -
|OS compatibility
|Windows, Linux
|ASDF installable
|Official Download
|Mirrored Download
|Source code repository
Ystok-URI is based on
URIs are represented by instances of a structure type. Percent-encoding/decoding is implemented in full. It is highly optimised for UTF-8 and supports other external formats basing on Lisp implementation-specific i18n/l10n functions or ACL-Compat.
The help book (documentation in HTML format) is at http://lisp.ystok.ru/yuri/help/help.html.
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subset: commoncrawl


text:
Hey there. You were asking about sandalwood perfumes, my two favorites are Bois de Iles by Chanel and Santal Noble by Maitre Parfumeur et Gantier. Both with beautiful sandalwood notes.
I just wanted to drop a note and say how much I enjoy reading your reviews! It was a such a pleasure discovering someone else loved Essenza di Zegna as much as I. I plan on sampling some of your other favorites and hope one of them become one of my favorites.
Thanks alot
Basenotes is an online guide to perfume and fragrance, featuring news, a database of fragrances, perfume glossary, fragrance forums, user reviews and more.


text:
+1The laws here in the south still need some work, but these steps are signs of progress. Props to Free the Hops in AL and Raise your Pints in MS for all their hard work to change antiquated laws.
There are three things I would like to see. 1) homebrewing prohibition lifted. 2) On premise sales for breweries. 3) Relaxation of some of the strict brewpub laws. Homebrew prohibition is going to fall in the next couple of years. The other two I'm not so sure about, especially the 2nd because it takes profits out of the hands of our distributors. But if we get those three lifted then there is not much more work that needs done.
One sour note: Arrogant Bastard has been denied in Al due to the name. (insert eyeroll).


text:
Gone Fishing...
January 30, 2012
I've been putting off the inevitable. But this morning, I took the plunge, and canceled my World of Warcraft subscription, almost 6 years to the day I started playing.
I haven't logged in since Christmas Day, when I logged in to pick up a few gifts for my alts under the Winter Veil tree. MIA were the many folks who've made the game fun for me. And thus I quickly logged off and went back to playing that other MMO.
I have 6 years of memories-- both amazingly awesome and incredibly disappointing-- behind me with this game. I don't think I can say the same for any previous game or online distraction.
And then there are those of you who are actually reading this post. The amazing online blogging and twitter community that has sprung up around this game over the years has been a prime motivator and instigator of so much of the fun I've had in game. I won't miss you guys b/c I am taking you along with me via twitter and the other blog.
I may be back for the next expansion, becuase I really am excited about my 150 vanity pets becoming Pokemon.
In the interim, I will still write about MMO guild management topics here when the mood moves me to do so.
But for now, I'm shifting out of the purple shadow form and hanging up my Boomkin dancing shoes for a bit.
Catch you on the flipside...


text:
Fruits of the Forest No-Churn Icecream
There are various versions of vanilla no-churn ice cream out there on the internet, and so far, I've liked Martha Stewart's
the best, but to be honest, we've been getting a bit bored of vanilla, so I decided to try making a Fruits of the Forest version with some homemade berry sauce. It is really yummy, but I can't wait until summer comes and strawberries are back in season because while this one was great, I think strawberry will be even better!
If you don't have berry sauce on hand, it is easy to whip some up - just heat 1 1/2 cups of frozen mixed berries with a few tablespoons of sugar and a dash of water for a few minutes until berries are soft. Cool before using.
Fruits of the Forest No-Churn Icecream
1 1/2 cups berry sauce
1 can (390g) sweetened condensed milk
1 tablespoon plum brandy (optional)
1 carton (600ml) cream
Stir berry sauce, condensed milk and brandy together in a large bowl until well mixed.
In another bowl, whip cream until stiff peaks form.
Gently fold cream into berry mixture.
Pour into freezer safe container and press a piece of baking paper onto surface.
Freezer overnight until firm.


text:
Justine is a little sailor boy, dressed in his finest for the parade. He brought his wood boat 'cause he's a natural Marine!
This porcelain soft body boy doll is the first issue in Yolanda Bello's Moments to Remember collection for Ashton-Drake 1992.
He comes Signed by the Artist, MIB, NRFB (except for signature), and pristine New!
Long dimension in inches. Height if the piece is taller than wide, width if vice versa.
We strive to ship within 24 hours of your purchase
Our simple shipping fee structure, which is based on your order total, makes shopping with us easy, reliable and affordable.
Our standard shipping is carried by USPS Retail Ground service.
|Order Total
|Shipping fee
|Up to $49.99
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* The above shipping fees are valid for destinations within the continental USA.
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text:
Another battle with a friend of mine, I normally play at least 3 games a week sometimes seven a week.
So lets get one with it. This is the first of three battle reports. So get ready to see some great Brikwarsing.
Set-up: as always I am ESF and I am going up against a friend.
I win the roll of and start my turn by moving up with all my units. I decided to test out a flamethrower for this battle report.
First casualty from my sniper rifle. This is pretty pathetic compared to what is to come. This was one of my favorite games.
I fail to kill anyone at this range pathetic really.
And of course they all get torched and killed with some well rolled sixes. All my heavy weapons guys are burned to bits now.
My soldiers charge in and attack ripping the enemy to shreds. Blood sprays everywhere and my lieutenant goes crazy slashing through every soldier with his chainsword.
An Overwatch of the dead and fighting.
My hero's head is taken of by a quick slice from the enemy hero, and they take the objective with is a weapons cache.
The enemy runs back and takes of one of my guys heads.
I kill her two rocket launcher dudes and feel quite accomplished.
My flamethrower works its magic. She loses another guy.
I send more soldiers back to their gods.
Blood flows and death covers the ground. Chainswords and power claws are held aloft as soldiers celebrate.
She almost has won only two more turns.
She continues to save her hero from death, really he's been hit by at least five shots with sixes. He still lives.
My epic flamethrower using his comrades skeletons as shields. Some think he loves his flamethrower. They are never seen again.
He places the flag and then is killed. She claims the cache and I lose. I was completely killed.


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Albums where: The second track is a continuation of the first / Track 1 should have been split into two
Trying to decide whether or not to split a track on our album release at the beginning. It was written as one, but has two very distinctive parts which share sonic themes, but one is instrumental whilst the other has vocals.
Trying to think of other bands who've done this to see what my reaction has been when they've done it.
Conversely, albums which start with one long song which could easily have been split into two.
Prelude & Inhaler off the new Foals album Holy Fire are a good example, though I'm drawing a blank on any more.
Anyway, go!
Jane Doe
Deloused In The Comatorium
Mars Volta!
Of course!
Is Jane Doe an artist or album
Pardon my ignorance. Chucking it in Spotify comes up with a lot of results.
Thanks for the suggestions though!
The first two on Jane Doe feel like distinct songs in their own right to me, even though the recording / feedback hang makes it sound like they were recorded in one.
see also first light / last light
from you fail me. i love that one though.
oh they tend to run them into eachother live too
they are seperate songs tho, i just only really like them together
as long as you don't call it 'intro'
when i did this i decided to split it into two because i felt like they needed different titles so that made it easy
Yeah, Intro / Prelude / Start all a bit meh
Personally I'm not so keen on the split so I'm trying to find counterexamples to know where it works well.
was about to say
Intro/Brave Men Run off Sonic Youth's Bad Moon Rising
Circuitry of the Wolf and Chinaberry Tree merge fairly seamlessly but are two separate tracks. I'd have had it as one.
I Break Horses go from Winter Beats to Hearts in the same way.
I'm not sure if they're exactly what you meant.
This is exactly what I'm looking for
The tracks in these two examples are a bit more distinct in their own right to the split decision I'm trying to make, but I'm just trying to get my head around my reaction to all sorts of examples where this happens.
Thoughts on splitting / mixing are:
1. Splitting them induces a short gap when you listen on an ipod or phone
2. Splitting them stops you taking both parts and using them in mixtapes (unless you manually merge them in something like audacity)
3. Splitting them means that live you wouldn't have to play the two in sequence to make sense in the context of an album
yeah was going to say the Mew one
also the first two tracks of Oceansize's Effloresce, kinda.
That Oceansize one kinda
Though I think the distinction between those two tracks is pretty clear, can't imagine concatenating them as one.
these Hands/January Twenty something.
They're basically two tracks, but you could definitely merge them.
Also the Maccabees last album had it,
with an instrumental opener merging straight into Child. That one really works as you can cut the intro out to listen to the song itself as a whole.
That Maccabees one's a great example
Really think it works. Sets the scene for the album, then starts a new track where it kicks in properly.
That Why coupling is defintely one
Where I didn't like the fact that they were split. I remember seeing the music vid to January Twenty Something for the first time and was wondering where the intro was. Hmmm.
Talk Talk - Spirit Of Eden
The first three tracks form a single continuous suite: it's had releases where they're a single track and others where they're split.
Good call
Didn't realise that they were one track in any incarnation though, you learn something new each day. Guessing with this one though it was more about the unmarketable nature (eugh) of a 23 minute track rather than actual distinction. Just a guess mind.
the third tracks quite different though.
the first two do flow together perfectly.
Not a first track but a last track
Folk Song Crisis by Seafood is effectivly one song split in two with the second half being a building chanty epic bit.
In terms of other places on albums
I was thinking of Dan Deacon who has a habit of putting a pretty extended coda onto whatever track is the "epic" one on that album.
Snookered / Of The Mountains
Wham City / Big Milk
Oh thought of a first track - Boxing Champion (pts 1 & 2)
by The Copperpot Journals is one track with two distinct halfs.
Don't think it's on spotify but try youtube.
Got it, makes me think it's the early 2000s again
Not actually 100% where one ends and the next starts but assuming it's the 2:58 mark where it scales back to a single guitar line. Seems like a good example of Parts 1 & 2 here. Thematically similar, tempo and style differ, distinct separations.Jordan_229_2 this'd this
Death In Vegas 'Scorpio Rising''s opening two tracks...
...Leather and Girls - would rather that Girls in particular was a separate track, and about twice as long.
Considering the amount of repetition in Leather
I would definitely separate these two, even if you've got ambient crossover between.
on silversun pickups second album
the first two tracks are separated but the second track starts before track 2 actually starts on the album? why they decided to tag the start of the second song at the end of track one i dont know?
So if you played track two on the CD
It'd jump in partway through the song?
pretty much
it has like this bit at the end of the first one for about a minute where he starts singing the lyrics from track number 2 and a different riff comes in then track two starts,
if you played track 2 without hearing the end of track 1 you wouldnt notice, but when you hear the end of track 1 its nothing to do with the riff from track 1 and the lyrics are part of track 2? haha
Weeds/Weeds II (The Origin of the Species)
on the last Pulp album
This Meshuggah album
The track changes about every minute...
New Mother by Angels of Light
has this.
The Fall do this a lot
There's Mansion/Bombast at the start of This Nation's Saving Grace, where the weird manipulated whines of Mansion lead into the thud of Bombast. It's brilliant.
Then there's Fortress/Deer Park on Hex Enduction Hour. The transition there is truly thrilling, one of my favourite things ever.
In both cases the first in the pair is slower, quieter, more experimental and you can almost feel the gathering of energy for the attack of the second. In both cases the second bit is the bit you remember but the first bit adds to the impact.


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Patterns On Wedding Dresses
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1:30 pm
Rudding Park
Rudding Lane, Follifoot, Harrogate, North Yorkshire, HG3 1JH
Multi-Manager Forum - Harrogate
This event has ended
Contributes to Structured Learning Time
Join Schroders and four other leading multi-manager providers at the Multi-Manager Forum.
Split across 16 venues throughout the UK, the forum gives you the chance to hear thought-provoking presentations, with an educational emphasis, covering the increased relevance of a multi-manager strategy within a volatile investment environment. The event is CII accredited and delivers two hours of structured CPD.
Date and Venue
12MAY 2015Rudding Park
Rudding Lane, Follifoot, Harrogate, North Yorkshire , HG3 1JH


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Camp and RV3 Now Available for iPad Users
October 4, 2010 by RVBusiness · Comments Off on Camp and RV3 Now Available for iPad Users
AllStays.com has taken its top-selling iPhone camping app called "Camp & RV" and rebuilt it to be a universal app for one price for all Internet Operating System (IOS) devices.
The new version adds a state and city manual search that works offline. The advantage of this is that even if RVers and other travelers don't have Internet service in the middle of a dense forest, they can still look ahead for camping options in another city on their trip, according to a news release.
Each location in the app has a detail view that includes a map, directions, phone number, a link to the official website and a easy way to report errors or make corrections.
If the camper is looking for something specific like state parks or national forest or just independently owned campgrounds, they can select to view only those on both the map view and the manual view. The app includes many filters for all kinds of camping along with various truck stops, outdoor sporting goods and supplies stores, rest areas, RV dealers, overnight parking spots, low clearance locations and some others. It also includes mapping and user reports for which Wal-Mart stores allow overnight parking for RVs and which do not.
"We had many requests to make Camp & RV available as a native app for the iPad," says Adam Longfellow, the owner of travel website AllStays.com. "So using the high-resolution, larger screen and full rotation capabilities of the iPad became a high priority. We listen closely to customer feedback. Almost every change we make is driven by user requests and suggestions."
When asked when the app would be available on Android devices, Longfellow said, "We want to try to support as many devices as possible and get our unique way of looking at and presenting camping information out to as many people as possible. The Android version will be released in the fall of 2010."
AllStays.com, based in Santa Fe, N.M., lists all kinds of lodging, from primitive campgrounds and RV Parks to luxury hotels and spa resorts. AllStays also links directly to official websites to make sure you have the real scoop on the latest and most accurate information.
For more information visit www.allstays.com.


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Transport 2017 in Herning (Danmark) will be held from 23 to 25 March 2017. On stand number H6044 VDL Bus & Coach will show the following vehicles:
Futura FDD2-141: a 14.1-metre-long double-decker. This double-decker offers both the discerning holidaymaker and the intercity business traveller a comfortable and fitting transport solution. The use of a newly developed upper-deck floor made of lightweight sandwich material has made it possible to achieve a generous 1.86 m of standing height on the lower deck. A true innovation is the improvement of the driver's upward viewing angle, achieved by sloping the floor of the upper deck upwards at the windscreen. This gives a feeling of having plenty of space and an optimal view. The FDD2-141 on show is fitted with 83+1+1 seating.
Citea LLE-99: a 9.9-metre version in a 27+2+1 configuration, specifically designed for sparsely populated areas and for scheduled services with clear peak and off-peak times.
Valkenswaard, mars 2017


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Style # 189735
Add bad-girl edge to your short collection with this bebe jeather short, featuring four-pocket styling, hidden front zipper and cuffed hem. Team it with a silk blouse and tights to maximize your look.
- 55% cotton, 38% polyester, 7% spandex.
- Rise: 9" (23 cm). Inseam: 2" (5 cm). Leg opening: 22" (56 cm).
- Machine wash.
- Imported.
- Model is 5'9" and is wearing a US size 28.
Jeather Trouser Short is rated out of 5 by 2.
Rated 5 out of 5 by jessie_3 from Un-regrettable Purchase Some of the most amazing pieces you purchase just end up sitting in your closet waiting for the right event to bust out but these shorts come out ALL THE TIME. You can mix and match with pretty much anything. Best purchase ever.
Date published: 2012-08-10
Rated 5 out of 5 by pinkangel from Love It! "I got this at the store, and it's really hot! I have plenty of tops to wear it with, including a BEBE vest I purchased awhile back that looks incredible. You can wear it with a dressy vest, waist belt, hose and heels or try it with a bright colored top with long sleeves that flair. I also am going to wear with with combat boots and a sheer leopard top. I can't wait. It's a new staple for my wardrobe! Although I did purchase this a size bigger than I normally would, I'm glad I did. I normally wear a 26 or 27, but I took a 28 in this one because I wanted a little extra coverage down below! :) These shorts are hot! Get them while you can, especially if you live in a warm climate. It would be great to also pair these shorts with a sequin top! It's so versatile."
Date published: 2012-06-09


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Come our usual time slot on Sunday, I'll be on a plane to San Francisco and the Game Developers Conference (GDC) so we're doing the iMore show early this week. And our very special guest will be Dieter Bohn of The Verge! We'll be talking about Apple's new hire, Kevin Lynch, the current competitive landscape, the idea of Google Now on iOS, and trying to read the Jony Ive tea leaves.
9am PT. 12pm ET. Be here!


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GULLANE, Scotland (AP) — Part defiant and part pragmatist, the head of the Royal & Ancient conceded Wednesday that all-male clubs are a bedeviling issue but insisted the British Open venues won't be pressured into opening their doors to women.
At his customary news conference on the eve of the British Open, R&A chief executive Peter Dawson faced a barrage of questions about the no-women-allowed membership at Muirfield and two other clubs in the nine-club tournament rotation, Troon and Royal St. George's.
He was prepared for the issue, reading from notes that made it clear he believes the issue does little harm to the game and has largely been contrived by the media, politicians and interest groups.
"Obviously the whole issue of gender and single-sex clubs has been pretty much beaten to death recently," Dawson said. "And we do, I assure you, understand that this is divisive. It's a subject that we're finding increasingly difficult, to be honest."
One reporter, touching on the racial discrimination that once pervaded the game, asked Dawson what was the difference between a male-only club and one that allowed only whites to join.
"Oh, goodness me, I think that's a ridiculous question, if I may say so," he replied. "There's a massive difference between racial discrimination, anti-Semitism, where sectors of society are downtrodden and treated very, very badly indeed. And to compare that with a men's golf club, I think, is frankly absurd. There's no comparison whatsoever."
He later added: "It's just kind of, for some people, a way of life that they rather like. I don't think in doing that they're intending to (bring) others down or intending to do others any harm."
Dawson emphasized that he doesn't believe gender-specific clubs stifle the growth of the sport. Still, he knows it's an issue that won't go away — especially since Augusta National admitted its first female members — so the organization that oversees golf outside the U.S. plans to address concerns once the Open is completed.
He wouldn't say what steps might be taken.
"Our natural reaction is to resist these pressures, because we actually don't think they have very much substance," Dawson said. "But I'd like to stress we're not so insular as to fail to recognize the potential damage that campaigns like this can do to the Open championship. And it is our championship committee's responsibility to do what is best for the Open, and to maximize the benefits which the Open brings, not just to golf, but also to the local area.
"When things are a bit quieter, after the championship," he went on, "I'm quite sure we'll be taking a look at everything to see what kind of sense we can make of it for the future. But I think right now our concentration has to be on this wonderful event and making it a success."
Eleven of the 24 questions to Dawson during the half-hour news conference revolved around the topic of male-only clubs. The issue of gender equity is squarely directed on golf's oldest major since Augusta National, home of the Masters, invited former Secretary of State Condoleezza Rice and South Carolina financier Darla Moore to become members last summer. Tiger Woods called it "important to golf."
Most golfers have shied away from the issue leading up to the Open, including the top-ranked Woods. When Rory McIlroy, the world's No. 2 player, was first asked about it Wednesday, there was a long pause and a forced smile before he said, "Muirfield is a great golf course."
Later, when someone asked McIlroy if the players had been advised not comment on the issue, he was more forthcoming.
"I just think it's something that a lot of guys don't want to get themselves into because it's quite a controversial issue," he said. "It's something that shouldn't happen these days. It's something that we shouldn't even be talking about."
Ernie Els said it's "weird" that some clubs won't admit both sexes, while Luke Donald said "we'd love to see these policies be a bit more inclusive."
"Wherever the governing bodies decide to play a tournament, it's my job to turn up and be ready and play, and that's what I am going to," Donald said. "I think the R&A is certainly trending in the right direction."
But some prominent Scottish politicians won't be attending this year's event in protest.
"I just think it's indefensible in the 21st century not to have a golf club that's open to all," said Scottish First Minister Alex Salmond, a huge golf fan who played a round with Phil Mickelson in the pro-am before the Scottish Open last week.
Two British government members — Maria Miller, the secretary of culture, media and sport, and sports minister Hugh Robertson — have also turned down invitations to attend.
Dawson said the R&A would not give in to political pressure.
"We've been through over 250 years of existence without getting into political comment, and I don't really intend to break that rule here," he said. "We've got politicians posturing; we've got interest groups attacking the R&A, attacking the Open, and attacking Muirfield."
While conceding that some changes are likely, Dawson made clear he believes the issue has largely been manufactured by those who don't necessarily have the best interests of the game at heart. He claimed there are very few gender-exclusive clubs in Britain, and that half of those are female-only.
"You can dress it up to be a lot more, if you want," Dawson said. "But on the Saturday morning when the guy gets up or the lady gets up and out of the marital bed, if you like, and goes off and plays golf with his chums and comes back in the afternoon, that's not on any kind of par with racial discrimination or anti-Semitism or any of these things.
"It's just what people kind of do."
Follow Paul Newberry on Twitter at www.twitter.com/pnewberry1963


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No need to fight over this special, there is plenty to go around!
Please remember to use your reef club's 10% discount code. Enter code 99869 in the view cart section above Paypal checkout logo.
All reverse osmosis systems should get the filters replaced at least annually. If you have poor water to begin with, you may need to change out more often. Our high quality FilmTec membrane will last from three to five years.
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Just enter the code 99920 in the "VIEW CART" section of the checkout cart and $1 will be added to cart, we will ship the extra filter pack for the unit you bought for no additional shipping cost. You can combine your 10% club discount code with the Quarterly Special !!
1st enter your clubs 10% discount code which is 99869
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Like us on Facebook: Air, Water & Ice, LLC for product specials, news, DIY tips on installation.
Air, Water & Ice - Water Filtration & Treatment, Aqaurium Filtration - Fort Pierce, FL | Facebook
Sincerely, The Staff at Air, Water & Ice


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Mobile x-ray set, London, England, 1920-1930
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Glossary: x-rays
A wave of electromagnetic radiation that has high energy and short wavelength. It is able to pass through many materials, except those of high density such as metals or bones. Discovered in 1895 by William Roentgen.
Glossary: mobile x-ray set
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USC returned to practice Sunday with a light workout and was buoyed by the return of wide receiver Marqise Lee, who ran during the workout and wore a small brace on his sprained knee.
Trojans coach Ed Orgeron said Lee was questionable for Saturday's game against Notre Dame.
Perhaps as significant for USC, tailback Tre Madden also participated in some of the practice after pulling his hamstring against Arizona on Thursday. Orgeron said Madden is probable against Notre Dame.
Wide receiver Darreus Rogers (sprained ankle), out since the Boston College game, is expected to return. Tight end Xavier Grimble (shoulder) is also probable, Orgeron said.
Cornerback Anthony Brown, out since the season opener against Hawaii with a sprained knee, could play this week and defensive end Morgan Breslin (hip), who did not play last week, should return.
Memory lane
One thing Orgeron's done since being named coach is reintroduce memories and practices of former USC coach Pete Carroll, including showing the Trojans highlights of games from the glory days of the Carroll era.
"Coach O brought Coach Carroll back," offensive tackle Kevin Graf said. "It means a lot to me."
No more late nights
Another change instituted by Orgeron is that the coaching staff goes home by 10 p.m. each night.
"We stopped working late at night," he said. "We went out and gave our coaches the opportunity to be fresh and coach with energy on the field."
Third-down improvement
USC was 6 for 13 on third downs (46 percent) against Arizona, which was its best performance of the season. For the season the Trojans are successful just 31 percent of the time, which ranks 106th nationally.
One reason USC might be better on third down now is because more players are touching the ball.
"Everybody feels like they have a role, everybody feels like they can contribute," athletic director Pat Haden said. "That's a really good thing."
USC a slight underdog
Notre Dame is a 2.5-point favorite over the Trojans. The Irish won two of the past three meetings against Lane Kiffin after Carroll went 8-1 against Notre Dame.
Recruiting update
USC offensive line coach Mike Summers attended the Alemany of Mission Hills-Loyola of Los Angeles game on Friday night and was apparently impressed with Loyola offensive tackle Chris Brown, who received a scholarship offer Sunday.


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Department of Revenue News Release
February 27, 2009Revenue Dept. To Extend Tax Deadlines for Southern MO Citizens Affected By Ice Storms
CAPE GIRARDEAU – Karen King Mitchell, director of the Missouri Department of Revenue, today announced that the deadlines to pay certain state taxes have been extended to help people and businesses cope with the recent ice storms and power outages that ravaged southern Missouri.
"A wide portion of southern Missouri was devastated by the ice storms in January," Mitchell said. "I know that many people went days or weeks without electrical power, and that their lives were disrupted in a major way. Because of these conditions, the department has decided to give people additional time to pay certain taxes they might owe."
Mitchell made the announcement this morning at Marquette Tower in downtown Cape Girardeau.
The deadline extension applies to state sales and income taxes due between January 22, 2009 and March 20, 2009. The deadline to pay the taxes has been extended to March 30, 2009.
Examples of taxes covered by the department's extension include:
- Missouri Sales Tax
- Corporate Income and Franchise Tax
- Missouri Employer Withholding Tax
The department has also decided to waive any penalties or interest connected with the late filing of fuel and cigarette taxes that businesses were required to remit to the state.
Taxpayers submitting returns past their original due dates should write "LATE DUE TO ICE STORMS" at the top of their return. Taxpayers that have already filed their taxes past the original due date should write a letter to the department explaining their taxes were filed past the due date as a result of the recent ice storms and request a waiver from any interest and penalties due to the late filing.
The department's directive does not apply to any federal or local taxes not collected by the department. It also does not change the April 15 deadline for paying Missouri income taxes due for Tax Year 2008.
Ctizens and businesses located in the 20 Missouri counties included in President Barack Obama's Feb. 17 disaster declaration are covered by the Department of Revenue's extension. The counties are Bollinger, Butler, Cape Girardeau, Carter, Dunklin, Howell, Madison, Mississippi, New Madrid, Oregon, Ozark, Pemiscot, Reynolds, Ripley, Scott, Shannon, Stoddard, Stone, Taney and Wayne.


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Nights like this
Nights Like This
70 Pine
70 Pine, Downtown Manhattan
Glory Days
Glory Days
Fire in the sky
A Night On The East River
Above South Street, NYC
Greased Lightning
"Why this city is automatic,
It's systematic,
It's hydromatic...
Why it's grease lightning!!!"
Weird Science
Weird Science
NYC Colors
NYC Colors
statue of liberty sunset
statue of liberty sunset
Tribute In Light
Manhattan Tower-Edit-Edit
Never Forget
Last one from my 9/11/14 folder
9/11/14 From the roof
9/11 tribute lights
Project Management
Brooklyn Bridge, NYC
Hell Gate
Hell Gate_
NYC, Macy's Fireworks 2014
Macy's Fireworks
I'm glad I managed to grab this shot from a moving car on the BQE. I also have around 20 blurry pictures I'll be posted later, so look out for those ;)
Manhattan Sunset
Manhattan Sunset_
Brooklyn Bridge and the FDR Drive
Viewed from Manhattan Bridge
Liberty State Park
Sightseeing in New York City.
Setting Sun
Morning Light
NYC skyline
Stormy Weather
One WTC
Early Bird Special
Welcome To New York City
Viewed from New Jersey
I love NY
Sunrise viewed from New Jersey.
The Bridge
Up Above
Lincoln Fruit Loop
NYC sunrise
Did you know there's a little red lighthouse under the GW bridge?
little red_
NYC Holiday Pano
NYC Holiday Pano
Shine On
Shine On
The Hideout
The Hideout
Lights and Stripes
Lights and Stripes_
Super Bowl Traffic
Super Bowl Traffic_
They'se some bright-ass lights
They'se some bright-ass lights
Super Bowl Super Bridge
The George Washington Bridge is lit up in Bronco orange and Seahawk green for the Super Bowl. This is the first time I've seen the towers lit in person. They only light them for special occasions. I heard it cost something crazy like $12,000 a day to light them.
New York City Skyline
GW Bridge In October
Breast cancer awareness month
Happy New Year!
Happy New Year!
ESB Dressed For The Holidays
Autumn on the Hudson
GW Bridge
Standing Strong
Standing Strong
aerialarchitecturebirds eye viewblue hourbrooklynbrooklyn bridgecityscapeeast riverempire state buildingmanhattanmanhattan bridgenew yorknynycpanopanoramapanoramic viewsunsettravelwilwilliamsburg bridgeworld trade center