text:
Behçet's disease: from Hippocrates to the third millennium
D H Verity1,
G R Wallace2,
R W Vaughan3,
M R Stanford1
1St Thomas's Hospital, London, UK
2Birmingham and Midland Eye Centre, Birmingham, UK
3Clinical Transplantation Laboratory, Guy's, King's and St Thomas' Hospital Medical Schools, London, UK
Correspondence to: D H Verity and M R Stanford, Medical Eye Unit, Thomas's Hospital, London, UK; veritydh{at}hotmail.com
Behçet's disease (BD) is characterised by recurrent episodes of orogenital aphthae, systemic vasculitis, and systemic and retinal venous thrombosis. An association between HLA-B51 and BD was first identified over 20 years ago, but recently identified gene associations implicate regions both within and without the MHC in the immunological events underlying the lesions in BD. These include allelic variants within the tumour necrosis factor gene region and within the MHC class I chain related gene region, the factor V Leiden mutation, which is associated with retinal vascular occlusion, and alleles of the intercellular adhesion molecule gene. No single causative gene for BD has emerged; the evidence indicates that the underlying immune events in BD are triggered by a microbial antigen and subsequently driven by genetic influences which control leucocyte behaviour and the coagulation pathways. Knowledge of these risk factors may permit a more accurate prognosis for a given patient, and identify new pathways for more targeted intervention than is currently available.
gene polymorphisms
retinal vascular occlusion
uvei
Behçet's disease owes its name to the Turkish physician professor Huluci Behçet, who, in 1937, described the classic trisymptom complex of hypopyon, iritis, and orogenital aphthosis.1 The Greek physician Adamantiades had reported the disease 6 years earlier, accounting for the alternative eponym Adamantiades-Behcet disease.2 However, the first description probably predates both of these by 2500 years. In his Epidemion, book 3, case 7, Hippocrates of Kos (460–377 bc) describes an endemic disease in Asia Minor characterised by "aphthous ulcerations," "defluxions about the genital parts," "watery ophthalmies of a chronic character . . . which destroyed the sight of many persons," and "large herpetic lesions."3 No further reference to the disease is encountered in the medical literature until the early 1900s, when the classic trisymptom complex was again described in Europe. At first, this complex was considered to be a manifestation of syphilis, but in 1937 Behçet proposed a separate disease entity, which, by 1947, had gained widespread international recognition. In the absence of a diagnostic laboratory test, Behçet's disease still remains a clinical diagnosis, and for the purposes of international research the diagnostic criteria proposed by the International Study Group in 1990 are now widely accepted (Table 1).4
International Study Group criteria for Behçet's disease
OCULAR DISEASE
Widespread organ involvement in Behçet's disease is now well recognised (Fig 1), although the clinical course and degree of organ involvement is often similar in successive relapses for a given patient. Inflammatory eye disease occurs in approximately 70% of all patients, and although it typically occurs after the onset of oral aphthosis, the delay between the two may be as long as 14 years.5 Conversely, intraocular inflammation is the presenting feature in over 10% of patients,6 and in rare cases oral aphthosis may not occur at all.7 The majority of ocular cases eventually suffer bilateral disease, but in 6% of cases, disease remains uniocular.8 Features of acute intraocular inflammation and the sequelae of recurrent episodes are given in Table 2, and Figures 2–4. It is of great interest that, while oral and genital aphthosis occur frequently in Behçet's disease, conjunctival ulcers are rarely encountered. Indeed, in a recent series of 1000 Iranian patients, conjunctival ulceration was described in only one individual,9 and in a recent Japanese study only four of 152 patients developed conjunctival ulceration over a 5 year period.10 This paradoxical sparing of the conjunctiva, and the complete absence of respiratory mucosal lesions, supports a role for infectious agents in the gastrointestinal tract in initiation and perpetuation of disease (see below).
Ocular features of Behçet's disease
Spectrum of organ involvement in Behçet's disease.
Anterior segment complications of retinal vein occlusion: retinal ischaemia with secondary rubeosis iridis.
Inflammatory retinal vein occlusion with associated vitritis and retinal vasculitis before (A) and after (B) treatment with high dose oral steroid.
(A) Acute branch retinal vein occlusion. (B) Total vascular obliteration and optic atrophy secondary to recurrent vascular occlusion.
The prognosis for vision in patients with recurrent posterior segment disease may be dismal, chiefly because of inflammatory retinal vein occlusions and macular oedema. In 1993, up to a quarter of eyes became blind.11 This dismal statistic has been reduced by modern immunosuppressive agents and more targeted immunomodulators, but up to 15% of ocular patients remain resistant to intervention.12 Cyclosporine, tacrolimus (FK 506), azathioprine, and anti-T cell monoclonal antibodies have all proved useful in controlling ocular disease in the short term, but their effect over the duration of active eye disease, which may be two to three decades, remains unproved.13–16 However, with increasing knowledge of the immune events that underlie Behçet's disease, newer interventions have become more targeted. Activation of neutrophils and leucocyte production of both IL-8 and tumour necrosis factor (TNF) are examples of pathways that may targeted. Blockade of TNF with infliximab, a chimeric anti-TNF-α monoclonal antibody, is effective in diminishing the severity of systemic Behçet's disease,17 and early reports on the effect on ocular disease are also promising.18,19
Recently, recombinant human interferon α-2a (rhIFNα-2a) has been employed in cases of refractory uveitis in Behçet's disease with promising results.20,21 Kötter et al investigated the efficacy of subcutaneous rhIFNα-2a in 50 patients with highly resistant ocular Behçet's disease, and reported a response in all but four patients.21 Equally significant is the finding that in 20 patients (40%), therapy could be discontinued after a mean period of 16.4 months without relapse over a mean observation period of 29.5 months. However, the mechanism of action of interferon in this context remains uncertain. IFN is known to inhibit γδ+ T cells,22 which have been implicated in the gastrointestinal lesions in Behçet's disease, and in addition has antiviral properties, which may be relevant given a possible role for herpes simplex virus in disease. Both of these aetiological factors are discussed below. Finally, rhIFNα-2a may downregulate IL-8 production by activated neutrophils, although paradoxically neutrophil adhesion and phagocytosis are reported to be increased following IFNα-2a treatment in patients with Behçet's disease.23 Further studies are therefore awaited to elucidate the mechanism of action of IFNα-2a in ocular Behçet's disease.
Behçet's disease is a systemic perivasculitis, in which early neutrophil infiltration, endothelial cell swelling, and fibrinoid necrosis are well described.24 Significant neutrophil infiltration is seen in all early lesions, including mucocutaneous aphthae, the skin pathergy reaction (in which minor trauma triggers a rapid cutaneous inflammatory response), nodular cutaneous lesions, and ocular lesions.25,26 In addition, serum levels of neutrophil priming cytokines such as TNF, interleukin 1 β (IL-1β) and IL-8 are known to be raised in patients,27 and myeloperoxidase levels, generated by active neutrophils, are also raised.28 Whether neutrophil hyper-reactivity in Behçet's disease reflects genetic influences or persistent activation by external priming agent(s) remains unresolved, although data from studies on familial Mediterranean fever (FMF), which shares features with Behçet's disease and is encountered in similar geographic regions, suggest that neutrophil responses are indeed under genetic control, as discussed below.
BEHçET'S DISEASE—AN INFECTIVE AETIOLOGY?
Although a microbiological trigger may underlie the innate immune response at the mucosal surface in Behçet's disease, the mechanism(s) for the vasculitis which follows (for example, inflammatory retinal vein occlusion) remain unknown, although they are not thought to have a direct microbial aetiology. The distribution of Behçet's disease in countries between the Mediterranean and the Orient, and its virtual absence in indigenous Amerindians and among populations south of the equator is intriguing29 (Table 3). Early trade routes between the Mediterranean and the Orient (the Silk Roads) promoted both commerce and the spread of disease, as exemplified by the plague of Athens in 430 bc, and the Black Death (Yersinia pestis) in the 14th century, the cause of the worst pandemic of the Middle Ages.30 According to the Hippocratic description, Behçet's disease may have been endemic in Asia Minor. No further descriptions emerge in the literature for two millennia, yet in the past 20 years a dramatic increase in reporting has occurred across southern Europe, Eurasia, and the Arabic world. This may reflect a reporting bias as the distinction between Behçet's disease and both syphilis and tuberculosis became appreciated. Equally, the rise in incidence may be real, and may be the result of contributory environmental agent(s). Indeed, both Behçet and Adamantiadis suspected an infectious aetiology, and two areas of research now support a microbial role in the disease.
Association between latitude and prevalence of Behçet's disease (adapted from Demirkesen et al25)
Firstly, skin and peripheral blood monocytes have been shown to exhibit a hypersensitivity response to certain Streptococcus sanguis antigens in patients but not in healthy controls.31 These bacterial antigens share amino acid sequences in common with one of the class of cell membrane proteins called heat shock proteins (HSP), which are expressed on cell membranes in response to physiological shock and microbial challenge. Several groups have demonstrated that both Streptococcus sanguis and the human HSP (especially the 60/65 kDa HSP) activate γδ T cells in patients but not controls.32,33 This observation has led to the suggestion that, following bacterial challenge, oral mucosal cells express HSPs which are antigenic and lead to antimucosal T cell cross reactivity in susceptible individuals (the molecular mimicry model). The observations that oral aphthae typically precede the onset of systemic disease by months or years,34 and frequently herald disease relapses, provide circumstantial support for this model. In addition, prophylactic penicillin has also been reported to reduce the frequency and duration of mucocutaneous symptoms of disease in a Turkish population.35 However, Behçet's disease is rare, streptococcal species are common oral fauna, and HSP are ubiquitously expressed by stressed cells. This model would require an escape of T cell clonal deletion (or positive selection) in the thymus in Behçet's disease or, alternatively, irregular leucocyte behaviour at the mucosal surface in patients, which may itself be influenced by certain HLA types. This second scenario is discussed at greater length later.
Behçet himself had proposed an aetiological role for herpes simplex virus (HSV) in the disease. Serum antibodies to HSV-1 and circulating immune complexes with HSV-1 are both reported to be raised in patients.36 Secondly, an animal model for Behçet's disease was described in 1997, in which 30% of HSV-1 innoculated mice were reported to exhibit Behçet's disease-like symptoms, which included skin, tongue, gastrointestinal and genital ulcers, and ocular inflammation and arthritis.37 Although HSV-1 immunity is common in the general population, the possibility exists that certain genetic haplotypes may influence the immune response of an individual to HSV-1 infection at the gastrointestinal mucosal surface. However, until such evidence arises, any role for HSV-1 in the pathogenesis of Behçet's disease remains speculative.
HERITABLE RISK FACTORS FOR BEHçET'S DISEASE
Behçet's disease is not a monogenic disorder, and no clear Mendelian pattern of inheritance has yet emerged. Nevertheless, a number of features point to a genetic aetiology. The unusual geographical distribution of disease and its close association with the major histocompatibility complex (MHC) allele HLA-B51 (see below) are perhaps the strongest indicators that certain gene(s) are either directly responsible for disease, or promote indirectly the characteristic underlying inflammatory changes. Furthermore, familial aggregation in Behçet's disease is well recognised. Recently, Gül et al reported the sibling recurrence risk ratio (λs) among patients in Turkey.38. λs is an indicator of the degree of familial clustering, and is a comparison of the risk of disease in the sibling of a patient compared to the risk for an individual in the general population. The λs value (11–53) in the Turkish population was reported to be higher than for a variety of other diseases considered to have complex genetic origins, including type 1 diabetes mellitus and rheumatoid arthritis. Although shared environmental factors could contribute to familial clustering, these high λs values unequivocally support a hereditary basis to Behçet's disease. Further evidence for hereditary risk factors is the finding of genetic anticipation in Behçet's disease, in which earlier disease onset is encountered in children of affected parents.39
HLA-B51 and the Silk Road
A heritable risk factor for Behçet's disease was first identified in 1982, when an association with HLA-B5 in the human MHC was first reported.40 The HLA-B*5 locus includes the family of HLA-B51 alleles and HLA-B52. In the great majority of racial groups, the greatest heritable risk factor for disease, and indeed for ocular disease severity, is HLA B51.41 Recent data indicate that while at least 21 different alleles may exist at the HLA-B*51 locus (B*5101, 5102, etc—asterix denoting modern molecular typing), both B*5101 and B*5108 are associated with disease.42 However, HLA-B*52, which differs from HLA-B*51 by only two amino acids in the peptide binding groove, is not associated with Behçet's disease in any population, suggesting that selective peptide binding, which is expected to differ between B*51 and B*52, may influence disease risk. However, it remains unclear which specific peptides, if any, are bound by B*51.
The geographical distribution of disease, encountered mainly in countries spanning the Mediterranean basin and the Far East, led to the synonym of Silk Road disease. These regions lie between latitudes 30° and 45° north, and it is of interest that the reported prevalence of Behçet's disease is associated with latitude and is rarely encountered in more northern climes, the Americas, and Australasia29 (Table 3). Furthermore, the geographical distribution of HLA-B*51 among healthy subjects roughly corresponds with global disease distribution (Fig 5); in countries in the southern hemisphere (for example, Africa, South Pacific), and in Europe above 45° N, the prevalence of HLA-B*51 in healthy individuals is low or nil, with a similarly low reported rate of Behçet's disease. This association between geographical disease distribution and HLA-B*51 has invoked the widely held belief that genetic risk factors were propagated by migrant traders along the Silk Road 2000 years ago. However, a more likely explanation is that the global distribution of associated gene(s) such as B*51 reflects not the passage of traders, but the earlier demographic movements across Asia and the Beringia Landmass (now the Beringia Straits) some 10 000 to 30 000 years ago. Since Africa, Eurasia, and the Americas had been populated by Homo sapiens by 300 000 bc, the virtual absence of HLA-B*51 in certain indigenous peoples (South Pacific and South American populations) indicates that HLA-B*51, and genes in linkage with B*51, must have been spread from West to East by subsequent migrations of peoples whose path broadly reflects the global distribution of Behçet's disease.29
Global distribution of HLA-B51 among healthy ethnic control groups with reference to the Silk Road and early demographic movements.
Thus, where HLA-B*51 is common, Behçet's disease is encountered, and where this allele is rare, so too is disease. Indeed, a recent study of eight microsatellite markers in the MHC region in three dissimilar ethnic groups confirmed that the only significant association with disease for all groups was with HLA-B*51, leading to the conclusion that HLA-B*51 itself is the pathogenic gene.43 However, HLA-B*51 cannot be the sole causative factor for the simple reason that roughly a third of patients, even in countries with a high disease prevalence, do not possess this gene. Furthermore, the risk, or odds ratio (OR), of Behçet's disease in an individual positive for HLA-B*51 shows a wide variation across Europe and Asia.29 A possible explanation for these data is that the HLA-B*51 molecule expresses the Bw4 motif, which itself may be causally related to disease, and which is found in other HLA types variably associated with Behçet's disease, including HLA-B*15, HLA-B*27, and HLA-B*57.44,45 However, convincing evidence for a direct role for any of these molecules in Behçet's disease is still awaited, and an alternative explanation is that these genetic domains are identified as markers for other associated "disease genes" within the MHC, as discussed below.
Other MHC associations with Behçet's disease
Tumour necrosis factor
Over the past 20 years many new genes have been identified between HLA-B and the complement cluster. This area is densely packed with genes which encode proteins with immune related functions, including the complement system proteins, tumour necrosis factor (TNF), the heat shock protein (HSP) family, and the MHC class I chain related genes (MIC) (Fig 6). Certain allelic variants within these genes (polymorphisms) are in linkage disequilibrium with class I alleles (that is, these genes are more likely to be inherited than occur by chance alone), and their influence on the immune system has generated considerable interest in the context of MHC related inflammatory diseases.46 TNF is one such example of a gene domain close to the HLA class I region, and the contribution of TNF gene polymorphisms to MHC associated diseases has been thoroughly investigated. In 1992, an association between Behçet's disease and alleles in the TNF promotor region was first reported in Japanese patients with Behçet's disease,47 an association that has recently been confirmed among Middle Eastern patients.41 Two possible alleles may exist at the promotor site: TNFB*1 and TNFB*2. The latter is associated with higher TNF production by stimulated monocytes than the former and is not only more prevalent among patients with Behçet's disease but is also weakly associated with a poor visual outcome.41 Although neither allele is rare, TNFB*2 has been associated with higher leucocyte TNF production, and might therefore lead to a more severe and prolonged inflammatory response. However, the TNFB*2 allele is also in linkage with HLA-B51, and these two alleles may therefore be co-inherited, each contributing both to disease risk and to severity of organ involvement.
The human major histocompatibility complex (MHC) on the short arm of chromosome 6. TAP = transporter of antigenic peptides; 21-OH = steroid 21-hydroxylase enzyme; C4A and B = complement loci; Bf = properdin factor B of the alternate complement pathway; C2 = complement C2; TNF = tumour necrosis factor; MICA = MHC class I chain related gene; LT = lymphotoxin.
MHC class I chain related (MIC) gene
A second gene in linkage with HLA-B51 is the MHC class I chain related (MIC) gene. The family of MIC genes, first reported in 1994, is situated in the region between TNF and HLA-B genes.48 The MICA gene encodes a polypeptide that is expressed predominantly on gastrointestinal epithelial cells, and has a predicted amino acid sequence similar to that of MHC class I molecules. This may be relevant in Behçet's disease, since oral and oesophageal lesions are a common and early feature, and MICA molecules are recognised by γδ T cells and natural killer (NK) cells. This is of interest because both γδ and NK cells have cytotoxic function and are increased in peripheral blood of patients with Behçet's disease,49 and γδ cells have also been recovered from the aqueous humour of patients.50 Moreover, a significantly increased proportion of γδT cells express activation markers (CD69, CD29), produce IFNγ and TNF, and in particular are upregulated in response to peptides derived from Hsp 65 in patients compared to controls.51–53
An association between MICA genes and Behçet's disease was first described in 1997, when it was shown that the prevalence of a certain "triplet repeat" polymorphism in the transmembrane region of the MICA gene (the MICA A6 allele) was raised in Japanese patients with Behçet's disease.54 In 1999, these findings were confirmed in a Middle Eastern population, and a second MICA gene, encoding part of the extracellular region of the molecule (the MIC 009 allele), was also found to be more prevalent among patients.55 The initial inference was that certain MICA alleles might influence MICA function, leading to abnormal interactions between infected epithelial cells and cytotoxic T cells in Behçet's disease. Hopes that MICA might be the long awaited Behçet's disease "susceptibility gene" faded, however, when subsequent analysis revealed a tight linkage between these alleles and HLA-B51, which itself remained the strongest genetic risk factor for disease. Behçet's disease cannot therefore be attributed to MICA alleles alone; nevertheless the position of MICA proteins in the GI tract and their recognition by γδ T cells strongly indicates that the inheritance of HLA-B51 linked MICA alleles may also influence disease risk (Fig 7). In support of a role in Behçet's disease, γδT cells have been shown to proliferate in response to supernatant from cultured micro-organisms obtained from an oral ulcer from a patient with Behçet's disease compared to healthy controls.56 In addition to the response to micro-organisms, γδT cells from patients also recognise the non-peptide prenyl pyrophosphate antigen,50 indicating that γδ T cells in Behçet's disease are in a primed state and may be involved in mediating pathogenesis.
Behçet's disease. Putative role of MICA molecules and HSP expressed on mucosal epithelial cells. *The MHC class I chain related (MIC) gene locus is situated adjacent to the HLA-B domain. MICA is of interest in Behçet's disease because it is expressed at gastrointestinal epithelial surfaces in response to bacterial infection. γδ T cells and NK cells are upregulated in Behçet's disease and are known to recognise and kill MICA transfected cells. Recently, MICA was shown to be a ligand for NKG2D which is also expressed on γδ T cells and NK cells. †Heat shock proteins (HSP) are expressed in response to cellular shock, and have been found on cells lining the gastointestinal tract. T cell responses to HSP derivatives are reported to be raised in patients, and the genetic promoter region for HSP expression is also known to control MICA expression.
NEW INSIGHTS INTO THE GENETIC BASIS OF BEHçET'S DISEASE
In recent years, newly identified non-MHC regions have been reported as risk factors for Behçet's disease. These discoveries further support a multigenic aetiology, and may disclose new therapeutic avenues.
Factor V Leiden and venous occlusion in Behçet's disease
Behçet's disease confers up to a 14-fold risk of developing systemic venous thrombosis (intracranial example, Fig 8), and the risk in males is reported to be six times higher than in females.57 In the eye, recurrent retinal vascular occlusion may occur in up to 48% of all ocular patients and is a major cause of visual loss in Behçet's disease. In 1994, a point mutation in the factor V gene on chromosome 1 was discovered in Leiden, Holland (the Leiden mutation) and is now recognised as the most common hereditary abnormality of the clotting system.58 It is a risk factor for idiopathic systemic venous thrombosis and has also been associated with Behçet's disease, in which systemic venous thrombosis occurs in up to 40% of all patients. Since 1996, this mutation has been reported to be raised among patients in Saudi Arabia59 and Turkey.60 More recently the mutation been associated with ocular disease, and in particular the development of ocular vaso-occlusion.61 This discovery indicates that genes outside the MHC may contribute independently to morbidity in Behçet's disease, and raises the question of whether anticoagulation in ocular patients with aggressive disease may play a part in managing these patients.
Intracranial venous thrombosis. (A) Male patient presents with headaches and disc oedema. (B) Magnetic resonance imaging and (C) magnetic resonance angiography demonstrating superior sagittal sinus thrombosis.
Intercellular adhesion molecule polymorphisms
The intercellular adhesion molecules (ICAM) are a family of receptors expressed on the surface of activated vascular endothelium. These molecules interact with their ligand molecules on leucocytes, enabling the movement of pro-inflammatory cells across the vessel wall into the tissues (see Fig 9). Once released from the endothelial surface, the soluble form of ICAM-1 (sICAM-1) may be detected in the peripheral blood of patients with a variety of inflammatory disorders, including Behçet's disease.62 The ICAM-1 gene is encoded on chromosome 19 and contains at least two positions of allelic variation. These sites probably encode structural parts of the ICAM-1 molecule, and variations in the DNA sequences at these positions may therefore affect the binding properties between ICAM-1 and its leucocyte receptors. Alleles at both positions have been associated with inflammatory diseases such as multiple sclerosis,63 inflammatory bowel disease,64 and renal allograft failure,65 and, more recently with Behçet's disease.66,67 However, until the effect of these allelic variants on the function of ICAM-1 is known, the relevance of these findings to Behçet's disease remains unclear. Furthermore, since the ICAM-1 gene alleles in question are common in control populations, their relative effect on ICAM-1 binding and their influence on the risk of developing Behçet's disease are likely to be small. Nevertheless, these findings also support a multigenic disease aetiology.
Behçet's disease. Factors affecting endothelial cell activation and leucocyte extravasation.
Behçet's disease, familial Mediterranean fever, and genetic control of neutrophils
Familial Mediterranean fever (FMF) shares a number of features in common with Behçet's disease. It occurs commonly in people of Arab, Turkish, or non-Ashkenasi Jewish origin, is characterised by recurring bouts of fever, peritonitis, arthritis, pleurisy and skin rashes, and may also lead to renal amyloidosis. Recently the gene associated with FMF was identified (MEFV), and the disease has been shown to be inherited in an autosomal recessive manner.68,69 The gene codes for a protein called pyrin, which is thought to be involved in regulating neutrophils in the inflammatory response. Several mutations in the MEFV gene have been identified and, given the ethnic distribution of FMF and the involvement of neutrophils in both diseases, these have been studied in patients with Behçet's disease. Four mutations have been shown to be more prevalent in patients with Behçet's disease (range 2.6%–10.5%) compared with control individuals (range 0%–2.2%) suggesting that MEFV mutations may act as susceptibility factors in Behçet's disease.70 Moreover, MEFV mutations present in the Middle East have never been reported in Japan, and it has been suggested that this might explain why amyloidosis seen in Behçet's disease follows the same geographical pattern.71 Finally, it is of interest that in those unfortunate individuals with a diagnosis of both FMF and Behçet's disease, only one MEFV gene mutation has been identified, suggesting that Behçet's disease can precipitate FMF (usually a recessive disease), in individuals with only a single MEFV mutation.72 Collectively, these findings indicate that (a)Behçet's disease activation of PMN is sufficient to overcome the heterozygous state of FMF carriers, and (b) an abnormal genetic influence on neutrophils which is responsible for FMF may also play a part in Behçet's disease.
Killing inhibitory receptors (KIR)
The most fundamental question in Behçet's disease research is how HLA-B51 is causally related to the inflammatory events at the mucosal and/or vascular endothelial surfaces. Recently, a new family of T cell receptors, expressed mainly by natural killer (NK) cells and γδ T cell receptor positive T cells (both implicated in Behçet's disease) has been described.73 This family of receptors is termed killer inhibitory receptors (KIR), and engagement of KIRs is known to inhibit cell mediated toxicity.74 One KIR (NKB1) binds to molecular sequences which are also found in some HLA class I molecules, including HLA-B51. An expansion of CD8+ cells, γδ TCR+ cells, and NK cells has been reported in patients with Behçet's disease, and more recently defective expression of KIR on NK cells in patients with Behçet's disease has also been reported.75 This has led to the suggestion that the host MHC class I haplotype (for example, HLA-B*51) may "fine tune" the regulation of KIR expression.76 Thus, KIR binding to sequences present in HLA-B51 expressed on gastrointestinal epithelial cells in patients with Behçet's disease may lead to a defect in the regulation of T cell inhibition or activation, and could in turn lead to abnormal responses to microbiological challenges at the epithelial surface.
Huluci Behçet himself postulated a viral trigger for this disease. Sixty five years later it remains unclear whether a virus or bacterium initiates and/or prolongs the characteristic mucosal and endothelial hyper-reactivity observed at the gastrointestinal and vascular endothelial surfaces, respectively. However, it has become increasingly apparent that these events, once triggered, may be influenced by numerous interdependent and independent genetic regions. Despite 20 years of intense efforts to identify other associated genetic regions in chromosome 6 and elsewhere, HLA-B51 remains foremost among candidate risk factors for disease (Fig 10). TNF and MICA alleles in the MHC are also implicated, but their close linkage with HLA-B51 has made their independent contribution to disease less easy to define. Newly characterised regions on different chromosomes may also contribute to disease, through their influence on the clotting cascade, on the events that underlie the leucocyte recruitment into the tissues, and on neutrophil activation. These discoveries have important implications for the management of patients with Behçet's disease. Firstly, they provide a rationale for new forms of immunomodulation that are now under investigation such as TNF and ICAM blockade, and interferon α-2a. In the case of factor V Leiden, anticoagulative measures, in addition to immunosuppression, may be valuable in managing patients with severe and recurrent ocular occlusive disease. Secondly, increasing knowledge of genetic disease severity markers may enable early identification of vulnerable patients before irreversible ocular complications ensue. This, in association with increasingly effective and targeted immune blockade, has every chance of improving the outlook of this blinding disease.
Behçet's disease is associated with multiple hereditory and environmental risk factors.
This work was funded by the Iris Fund for the Prevention of Blindness, the TFC Frost Charitable Trust, and the St John Eye Hospital in Jerusalem.
Behçet H. Über rezidiverende, apthöse durch ein Virus verursachte Geschwüre am Mund, am Auge und an der Genitalen. Dermatol Wochenschr 1937;105:1152–7.
Adamantiades B. Sur un case d'iritis á hypopyon récidivant. Ann Oculist (Paris) 1931;168:271–8.
Feigenbaum A. Description of Behçet's Syndrome in the Hippocratic Third Book of Endemic Diseases. Br J Ophthalmol 1956;40:355–7.
International Study Group for Behçet's Disease. Criteria for diagnosis of Behçet's disease. Lancet 1990;335:1078–80.
Lee E-S, Hur W, Bang D, et al. Prognosis of recurrent oral ulceration in Behçet's disease. In: Godeau P, Wechsler B, eds. Behçet's disease. Paris: Elsevier, 1993:291–4.
Dilsen N, Konice M, Aral O, et al. Risk factors for vital organ involvement in Behçet's disease. In: Godeau P, Wechsler B, eds. Behçet's disease. Paris: Elsevier, 1993:165–9.
Lueck CJ, Pires M, McCartney AC, et al. Ocular and neurological Behçet's disease without orogenital ulceration? J Neurol Neurosurg Psychiatry 1993;56:505–8.
Imai Y. Studies on prognosis and symptoms of Behçet's disease in long-term observation. Jpn J Clin Ophthalmol 1971;25:661–94.
Chams C, Mansoori P, Shahram F, et al. Iconography of mucocutaneous lesions of Behçet's disease. In: Godeau P, Wechsler B, eds. Behçet's disease. Paris: Elsevier, 1993:359–62.
Matsuo T, Itami M, Nakagawa H, et al. The incidence and pathology of conjunctival ulceration in Behçet's syndrome. Br J Ophthalmol 2002;86:140–3.
Howe L, Denman A, Dinning W, et al. Visual prognosis in Behçet's disease. In: Godeau P, Wechsler B, eds. Behçet's disease. Elselvier Science Publishers, 1993:599–602.
Muhaya M, Lightman S, Ikeda E, et al. Behçet's disease in Japan and Great Britain. Ocular Immunol Inflamm 2000;8:141–8.
Whitcup SM, Salvo EC Jr, Nussenblatt RB. Combined cyclosporine and corticosteroid therapy for sight-threatening uveitis in Behcet's disease. Am J Ophthalmol 1994;118:39–45.
Kilmartin DJ, Forrester JV, Dick AD. Tacrolimus (FK506) in failed cyclosporin A therapy in endogenous posterior uveitis. Ocul Immunol Inflamm 1998;6:101–9.
Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the treatment of posterior uveitis refractory to cyclosporine. Ophthalmology 1999;106:723–8.
Hamuryudan V, Ozyazgan Y, Hizli N, et al. Azathioprine in Behçet's syndrome: effects on long-term prognosis. Arthritis Rheum 1997;40:769–74.
Goossens PH, Verburg RJ, Breedveld FC. Remission of Behcet's syndrome with tumour necrosis factor alpha blocking therapy. Ann Rheum Dis 2001;60:637.
Sfikakis PP, Theodossiadis PG, Katsiari CG, et al. Effect of infliximab on sight-threatening panuveitis in Behçet's disease. Lancet 2001;358:295–6.
Triolo G, Vadala M, Accardo-Palumbro A, et al. Anti-tumour necrosis factor monoclonal antibody treatment for ocular Behçet's disease. Ann Rheum Dis 2002;61:560–1.
Stuebiger N, Koetter I, Zierhut M. Complete regression of retinal neovascularization after therapy with interferon alpha in Behcet's disease. Br J Ophthalmol 2000;84:1437–8.
Kotter I, Zierhut M, Eckstein AK, et al. Human recombinant interferon alfa-2a for the treatment of Behcet's disease with sight threatening posterior or panuveitis. Br J Ophthalmol 2003;87:423–31.
Metzger R, Heckl-Ostreicher B, Nerl C, et al. Immunological studies of gamma delta T cells in a case of large granular lymphocyte (LGL) leukemia: leukemic gamma delta+ T cells are resistant to growth stimulation in vitro but respond to interferon-alpha treatment in vivo. Leuk Res 1992;16:1087–95.
Karti SS, Ovali E, Ratip S, et al. Effect of interferon-alpha (2a) on neutrophil adhesion and phagocytosis in chronic myeloid leukeamia and Behcet's disease. Clin Rheumatol 200:21;211–14.
Ergun T, Gurbuz O, Harvell J, et al. The histopathology of pathergy: a chronologic study of skin hyperreactivity in Behçet's disease. Int J Dermatol 1998;37:929–33.
Demirkesen C, Tuzuner N, Mat C, et al. Clinicopathologic evaluation of nodular cutaneous lesions of Behçet's syndrome. Am J Clin Pathol 2001;116:341–6.
Tugal-Tutkun I, Urgancioglu M, Foster CS. Immunopathologic study of the conjunctiva in patients with Behçet's disease. Ophthalmology 1995;102:1660–8.
Mege J-L, Dilsen N, Sanguedolce V, et al. Overproduction of monocyte derived TNF, Interleukin (IL) 6, IL 8 and increased neutrophil superoxide generation in Behçet's disease. A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol 1993;20:1544–9.
Accardo-Palumbro A, Triolo G, Carbone MC, et al. Polymorphonuclear leukocyte myeloperoxidase levels in Behçet's disease. Clin Exp Rheumatol 2000;18:495–8.
Verity DH, Vaughan RW, Marr JE, et al. Behçet's disease, The Silk Road and HLA-B51: historical and geographical perspectives. Tissue Antigens 1999;54:213–20.
Parker G, ed. The commercial and cultural bonds of Eurasia. In: The Times atlas of world history. 4th ed. London: Times Books, 1993.
Kaneko F, Oyama N, Nishibu A. Streptococcal infection in the pathogenesis of Behçet's disease and clinical effects of minocycline on the disease symptoms.Yonsei Med J 1997;38:444–454.
Lehner T. The role of heat shock protein, microbial and autoimmune agents in the aetiology of Behçet's disease. Int Rev Immunol 1997;14:21–32.
Direskeneli H, Eksioglu-Demiralp E, Yavuz S, et al. T cell responses to 60/65 kDa heat shock protein derived peptides in Turkish patients with Behcet's disease. J Rheumatol 2000;27:708–13.
Bang D, Yoon KH, Chung HG, et al. Epidemiolgical and clinical features of Behçet's disease in Korea. Yonsei Med J 1997;38:428–36.
Calguneri M, Ertenli I, Kiraz S, et al. Effect of prophylactic benzathine penicillin on mucocutaneous symptoms of Behçet's disease. Dermatology 1996;192:125–8.
Sohn S, Lee ES, Bang D, et al. Behcet's disease-like symptoms induced by the Herpes simplex virus in ICR mice. Eur J Dermatol 1998;8:21–3.
Gul A, Inanc M, Ocal L, et al. Familial aggregation of Behcet's disease in Turkey. Ann Rheum Dis 2000;59:622–5.
Fresko I, Soy M, Hamurydan V, et al. Genetic anticipation in Behçet's syndrome. Ann Rheum Dis 1998;57:45–8.
Ohno S, Ohguchi M, Hirose S, et al. Close association of HLA-Bw51 with Behçet's disease. Arch Ophthalmol 1982;100:1455–8.
Verity DH, Wallace GR, Vaughan RW, et al. HLA and TNF polymorphisms in ocular Behçet's disease. Tissue Antigens 1999;54:264–72.
Mizuki N, Ota M, Katsuyama Y, et al. HLA class I genotyping including HLA-B*51 allele typing in the Iranian patients with Behçet's disease. Tissue Antigens 2001;57:457–62
Mizuki N. Ota M. Yabuki K, et al. Localization of the pathogenic gene of Behçet's disease by microsatellite analysis of three different populations. Invest Ophthmol Vis Sci 2000;41:3702–8.
Choukri F, Chakib A, Himmich H, et al HLA-B*51 and B*15 alleles confer predisposition to Behcet's disease in Moroccan patients. Hum Immunol 2001;62:180–5.
Gul A, Uyar FA, Inanc M, et al. A weak association of HLA-B*2702 with Behçet's disease. Genes Immun. 2002;3:368.
Ahmad T, Wallace GR, James T, et al. Mapping the HLA association in Behçet's disease: a role for tumour necrosis factor polymorphisms. Arthritis Rheum 2003;48:807–13.
Mizuki N, Inoko H, Sugimura K, et al. RFLP analysis in the TNF β gene and susceptability to alloreactive NK cells in Behçet's disease. Inv Ophthalmol Vis Sci 1992:33:3084–90.
Bahram S, Bresnahan M, Geraghty DE, et al. A second lineage of mammalian major histocompatibility complex class I genes. Proc Natl Acad Sci USA 1994;91:6259–62.
Nishida T, Hiruyama K, Nakamura S, et al. Proliferative response of CD8+ γδ T cells to Streptococcus sanguis in patients with Behçet's disease. Ocular Immunol Inflam 1998;6:139–44
Verjans GM, van Hagen PM, van der Kooi A, et al. Vgamma9Vdelta T cells recovered from eyes of patients with Behçet's disease recognize prenyl pyrophosphate antigens. J Neuroimmunol 2002;130:46–54.
Eksioglu-Demiralp E, Direskeneli H, Ergun T, et al. Increased CD4+CD16+ and CD4+CD56+ T cell subsets in Behçet's disease. Rheumatol Int 1999;19:23–6.
Freysdottir J, Lau SH, Fortune F. Gamma-delta+ T cells in Behçet's disease (BD) and recurrent aphthous stomatitis (RAS). Clin Exp Immunol 1999;118:451–7.
Hasan A, Fortune F, Wilson A, et al. Role of γδ T cells in pathogenesis and diagnosis of Behçet's disease. Lancet 1996;347:789–93.
Mizuki N, Ota M, Kimura S, et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet's disease. Proc Natl Acad Sci USA 1997;94:1298–303.
Wallace GR, Verity DH, Delamaine L, et al. Association with MICA alleles with Behçet's disease. Immunogenetics 1999;49:613–17.
Bank I, Duvdevani M, Livneh A. Expansion of gamma-delta T cells in Behçet's disease: role of disease activity and microbial flora in oral ulcers. J Lab Clin Med 2003;141:33–40.
Ames PR, Steuer A, Pap A, et al. Thrombosis in Behçet's disease: a retrospective survey from a single UK centre. Rheumatology 2001;40:652–5.
Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–7.
Mammo L, Al-Dalaan A, Bahabri SS, et al. Association of factor V Leiden with Behçet's disease. J Rheumatol 1997;24:2196–8.
Gül A, Ozbeck U, Ozturk C, et al. Coagulation factor V gene mutation increases the risk of venous thrombosis in Behçet's disease. Br J Rheumatol 1996;35:1178–80.
Verity DH, Vaughan RW, Madanat W, et al. Factor V Leiden mutation is associated with ocular involvement in Behçet's disease. Am J Ophthalmol 1999;128:352–6.
Verity DH, Wallace GR, Seed P, et al. Soluble adhesion molecules in Behçet's disease. Ocul Immunol Inflamm 1998;6:81–92.
Mycko MP, Kwinkowski M, Troncznska E, et al. Multiple sclerosis: the increased frequency of the ICAM-1 exon 6 gene point mutation genetic type K469. Ann Neurol 1998;44:70–5.
Yang H, Vora DK, Targan SR, et al. Intercellular adhesion molecule 1 gene associations with immunologic subsets of inflammatory bowel disease. Gastroenterology 1995;109:440–8.
McLaren AJ, Marshall SE, Haldar NA, et al. Adhesion molecule polymorphisms in chronic renal allograft failure. Kid Int 1999;55:1977–82.
Verity DH, Vaughan RW, Kondeatis E, et al. Intercellular adhesion molecule-1 gene polymorphisms in Behçet's disease. Eur J Immunogen 2000;27:73–6.
Boiardi L, Salvarani C, Casali B, et al. Intercellular adhesion molecule-1 gene polymorphisms in Behçet's disease. J Rheumatol 2001;28;1283–7.
The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17:25–31.
The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90:797–807.
Touitou I, Magne X, Molinari N, et al. MEFV mutations in Behçet's disease. Hum Mutation 2000;16:271–2.
Akpolat T, Yilmaz E, Akpolat I, et al. Amyloidosis in Behçet's disease and familial Mediterranean fever. Rheumatology 2002;41:592–3.
Livneh A, Aksentijevich I, Langevitz P, et al. A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behçet's disease (FMF-BD). Eur J Hum Genet 2001;9:191–6.
Lanier LL. NK cell receptors for polymorphic MHC class I molecules. In: Charron D, ed. Genetic diversity of HLA. Functional and medical implications. Proceedings of the Twelth International Histocompatibility Workshop and Conference. Volumes I and II. Sevres, France: EDK Publishing, 1997.
Steinle A, Li P, Morris DL, et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics 2001:53;279–87.
Shimoyama Y, Takeno M, Kashiwakura J, et al. Reduced KIR expression is associated with NKT cell expansion in patients with Behçet's disease (abstract 1318). Arthritis Rheum 1998;41:S252.
Mingari MC, Moretta A, Moretta L. Regulation of KIR expression in human T cells: a safety mechanism that may impair protective T cell responses. Immunol Today 1998;19:153–7.


text:
20 years on St. Mark's Place
You can catch this exhibit by photographer Jesper Haynes starting tonight at Gallery Onetwentyeight, 128 Rivington St.
I planned on requesting a quick interview with Haynes... but decided to run an excerpt from his blog instead:
In 1986, I moved to my apartment on 90 St. Marks Place, in New York's East Village. It was above the St. Mark's Bar & Grill where the Rolling Stones had just filmed the video for "Waiting on a Friend". It was to be my home, and the backdrop for much of my photography, for the next 20 years.
In those days St. Marks was a rough place. It bustled with runaways and skate kids, with dealers and dime bag rappers and fabulously dressed low-lifes on their way to or from an after-hours club.
... however, life at St Marks began to change. The local fleabag movie house became a Gap clothing store. The Korean delis were replaced by Starbucks. Whole blocks were renovated and gentrified. St Marks was becoming hip. Rents began to rise and the artists, inevitably, started moving out.
My turn came in 2006 when my landlady, with whom I had developed a very close friendship, died. Her daughter inherited the building. Being a businesswoman, in a city that was now all about business, she saw the chance of higher rents and a different breed of renter. She duly gave us a three-month notice of eviction.
I still dream of that apartment and the intense, beautiful, often riotous, times I had there.
These photographs are an honest, spontaneous record of what I have lived and of the lives and loves for which my home in St. Marks became the setting.
[Jesper Haynes]
A few highlights from the week-long exhibit:
Opening Reception Thursday June 23 6-9 PM
Slide show, Book signing and Artist Q & A - Tuesday June 28 7 PM
Closing Party Thursday June 30 6-9 PM
Grieve at 6:47 AM
Is that last frame a photo of Mike Bloomberg pissing on NY ?
JM June 23, 2011 at 8:11 AM
1986 St. Marks Pl. was rough? Well, I guess, and certainly compared to today. What a fine, insane place it was, though. Everyone has a different New York in their hearts and that's mine, the '85-'93 version. And I still miss Theatre 80's double bills every time I walk by there.
Scott June 23, 2011 at 10:47 AM
Here's to another 20 years of riotous times without any riots.
Marty Wombacher June 23, 2011 at 12:46 PM
That last photo is classic! I definitely will check out the exhibit, thanks for the post!
Vivienne June 23, 2011 at 1:47 PM
That last photo is epic. This sounds like an awesome exhibit. Thanks for the information!
esquared™ June 23, 2011 at 3:14 PM
no different than st. mark's 2006-2026
but on that last picture, you have a pink shirt, khaki cargo shorts, brown flip flop wearing dbag vomiting, the people around him are woo-woooing, the women are wearing mini-skirts and stiletto heels while texting/reading from their "digital life support" and the street will be littered with cupcake wrappers and froyo-cups...
is that LES JEWELS from way back/when ????
Theater 80! Now-- that's the ONLY part of the EV of yesteryear that's genuinely WORTH mourning.
The first time I wandered in --about 1981 or thereabout-- I caught a random double feature of Sunset Boulevard & All About Eve. "These Theater 80 movies are pretty GOOD!", thought I; too stupid to know that I'd had the good fortune of stumbling in upon a double-feature of two of the greatest movies ever made.
Tom June 24, 2011 at 11:08 AM
Maybe it's miscommunication or misunderstanding, but some of Jesper's written remembrance seems to editorially side with the gentrification that's taken place, e.g.:
"The local fleabag movie house became a Gap clothing store."
That "local fleabag movie house" was St. Marks Cinema. It was worn, but hardly "fleabag". Moreover, it provided a valued service. Typically, it showed double features -- two second run movies for a little more than half the price of a single first run movie. I used to go to it more frequently than any other theater in the City. To not reference it by name, but dismiss it as a "local fleabag movie house" is wrong. I'd take St. Marks Cinema over a Gap store every day of the week.
Little Earthquake June 25, 2011 at 10:25 AM
"...a city that was now all about business..."
New York has ALWAYS been about business, since the Dutch bought it from the Lenape. There just wasn't much investment in St. Mark's in the 70s and 80s. But let's not kid ourselves about the nature of man, and this city.
Incidentally, the building in question was also used for the cover art of Led Zeppelin's Physical Graffiti.
Homeboy Steve March 4, 2012 at 3:44 PM
Sorry I missed the show.
Does anyone know where I might find a picture of the blue neon St Mark's Bar and Grill sign that was on the northeast corner of St Mark's & 1s Ave ?
Dean February 25, 2015 at 11:34 AM
My friend lived in that same apartment right over the St Mark's Bar & Grill in probably 1982. So many memories of hanging out on his fire escape over St Mark's Place and drinking and smoking up before heading downstairs to the bar.
I lived on the third floor of 90 St. Mark's Place in 1985.
I was 23 years old.
Me and my two room mates were among the first wave of gentrification of the neighborhood. We were all writers.
One wrote for Playboy, another for an ad agency, and me for a trade magazine.
Unlike the punker squatters who lived on the top floor, we actually paid rent and had running water.
The people in the neighborhood hated us because we represented the change that pushed them out.
Hard to believe a guy who earned $14,000 a year as a writer for Sporting Goods Business magazine could represent an influx of money and higher rent.
Anyway, after working all day on Times Square in a suit and tie, I'd come back to the East Village and dress all in black to join the other creatures of the night.
The Tompkins Park Riots took place that year, when the homeless "tent city" was torn down by the police.
Downtown Beirut bar was in full swing, along with The Aztec, and Grassroots Tavern. The Holiday Cocktail Lounge was the epicenter of it all, with $1.25 top shelf drinks.
Many of the buildings on St. Mark's were boarded up and condemned.
"Liz and Ronnie" stood on the corner of 1st and St. Mark's selling herb...till Liz just disappeared one day...probably dead.
I basically lived on one piece of pizza a day since all of my money went to rent and subway tokens.
It was probably the most colorful time of my life.
On weekend nights I'd go to Baird Jones' Underground club because it had no cover...or to The Ritz to see the Ramones...or the Cat Club to see Circus of Power and Cycle Sluts from Hell.
My friends would come into the city to visit me...and their eyes would pop out of their heads at the sights.
One night a fight spilled out of the St. Mark's Bar & Grill below us.
A skinhead and a longhair hippie were fistfighting in the street. The crowd watched and egged them on.
When they tumbled to the pavement and the skinhead tried to grab the hippie's hair, an onlooker knocked his hand away to make sure it was a fair fight...and let them continue.
That was the kind of mindset that existed on those mean streets.
Rarely did we ever venture past Tompkins Park into Alphabet City.
At that time we knew it could very well be a one-way trip.
Except on New Year's 1985...when we went to The World nightclub on Avenue C and 2nd Street to see The Ramones. The Beastie Boys, then unknown, were the opening act.
It was a scene that cannot be described.
This is Alex from Circus Of Power! Yes,they were great days🤓
Martin Farricker May 21, 2021 at 4:53 PM
ALEX! I saw you play with the Cycle Sluts at Cat Club one night when both bands played "Motoring" together. You guys ROCKED!!!!
Your remarks and lively debates are welcome, whether supportive or critical of the views herein. Your articulate, well-informed remarks that are relevant to an article are welcome.
However, commentary that is intended to "flame" or attack, that contains violence, racist comments and potential libel will not be published. Facts are helpful.
If you'd like to make personal attacks and libelous claims against people and businesses, then you may do so on your own social media accounts. Also, comments predicting when a new business will close ("I give it six weeks") will not be approved.

redpajama_set_name: RedPajamaCommonCrawl


text:
Tensions between police and Pride show a shifting target for progress | CBC News Loaded
British Columbia·FROM THE ARCHIVES
Tensions between police and Pride show a shifting target for progress
What was a moment of progress twenty years ago is not necessarily so for some activists in Vancouver's LGBT community today.
Enduring controversy around uniformed police officers in pride shows how progress shifts over time
Roshini Nair · CBC News · Posted: Aug 05, 2017 6:00 PM EDT | Last Updated: August 5, 2017
Revellers pose for a photos with police officers at the annual Pride Parade in Toronto in 2016. Black Lives Matter Toronto halted the parade that summer, requesting uniformed police officers be excluded from marching in the parade in protest of the Toronto Police's treatment of racialized groups. (Mark Blinch/Canadian Press)
Twenty years ago, members of Vancouver's LGBT community celebrated a milestone: for the first time in the history of the city's Pride parade, the chief of police would participate with a contingent of uniformed officers.
At the time, it was heralded as a mark of progress — a sign of approval from one of society's most conservative institutions.
In this report from July 29, 1997, then-CBC reporter Margo Harper marvelled at the contrast between the police as the "upholders of the status quo" and the marchers of the Pride parade as the "cutting edge" of society.
Vancouver's chief of police marches in 1997 in Pride Parade for first time
LGBT officers and guards discuss coming out at work.
Fast-forward twenty years and the subject of police in the Pride parade is a dramatically different conversation.
A new generation of LGBT activists have challenged the presence of uniformed officers in Pride parades across Canada.
These critics argue that the police uniform at the parade is a symbol of an institution that has harmed and continues to harm certain groups.
"When they march in uniform with weapons and vehicles as well, it can be traumatizing or triggering to people who have experienced police violence or their communities have experienced police violence," explained queer activist Cicely-Belle Blain, co-founder of Black Lives Matter Vancouver.
Blain's group is one of the more prominent ones opposed to police in the parade.
Police will march in Vancouver parade
Black Lives Matter Vancouver issued a set of requests earlier in the year to limit police participation in the summer Pride parade.
While the Vancouver Pride Society agreed to some of their requests — including no sirens used during the parade — it stopped short of removing all uniformed police officers from the parade.
Pride societies in other cities, like Calgary, have chosen to welcome police officers but have banned uniforms, official vehicles and floats.
Disappointed by Vancouver's stance, groups including Black Lives Matter Vancouver and Rainbow Refugee are sitting out of the parade.
'We can't close the door'
Velvet Steele, the VPD's LGBT advisor, says police officers deserve to be in the parade.
Steele says the VPD have put in efforts over the years to reach out to the LGBT community and the parade should be inclusive, not exclusive.
"I like to believe that Vancouver is leading by example. We are at the table with them discussing, making things aware to them to what's going on out there in the communities," she said.
"We can't close the door."
From left to right: Velvet Steele, who sits on VPD's LGBTQ advisory panel; VPD's diversity officer Const. Dale Quiring; and Seattle PD officer James Ritter. Over the past years, the VPD has implemented many programs and initiatives for the LGBT community. (Simon Charland-Faucher/CBC)
Sandy Leo Laframboise, an Indigenous trans activist who calls herself "one of the old activists from the 1970s," also supports uniformed police members in the parade.
"Is there a need to improve? Certainly," she said, recalling times when she herself was the subject of police intimidation and violence.
But for her, it's time to move on and allow the police their place in the LGBT community.
"Vancouver Pride is about celebration," she said. "Vancouver police — that's their identity, that's their outfit, that's their job."
'You can never take off your skin'
But Blain says conflating a uniform with an identity like race misses the point.
"I understand that people see it that police commit their lives to their jobs, but ultimately they can take off their uniforms at any time and they can remove themselves from the institution of policing at the end of their job and go out in plain clothes at any time," she said.
"If you're a person of colour, you can never be without that. You can never take off your skin."
Cicely-Belle Blain is the co-founder of Black Lives Matter Vancouver. (Alex Lamic CBC News)
A need to find common ground
Mary-Woo Sims, a queer activist and former chief commissioner of the B.C. Human Rights Commission, says the tension over uniformed police is understandable.
"If you think about the gay and lesbian community and the trans community, our history is full of incidents with the police," Sims said.
"It has not been a pretty picture. We have been bloodied. We have been arrested. Some of us still are."
Mary-Woo Sims says there's a lot more work to do to overcome the differences between members of the LGBT community. (Mikul Media 2014/ Vancouver Pride Society)
Sims says differing opinions on the subject are a reflection of the diversity of the LGBT community and the need to find common ground.
"Let's talk some more," she said. "What are we going to do in the future for better relations?"
With files from Jake Costello and Ethan Sawyer
Roshini Nair
Roshini Nair is a digital/coordinating producer with CBC Podcasts, working on series including Nothing is Foreign, The Secret Life of Canada, Kuper Island and more. She is based in Vancouver, and has previously worked on Party Lines: Party in the U.S.A., Unreserved, Unforked, and with CBC News Vancouver's digital news team.
LGBT refugees in Lower Mainland face service gaps
As Vancouver proclaims Pride Week, gay pioneer recalls city's first Pride Parade
Police commit to Calgary Pride march in plain clothes after ban on uniforms, parade float
Black Lives Matter leads alternative Pride march in Vancouver


text:
Isidro Gil Gabilondo lub Gavilondo – hiszpański malarz i rysownik pochodzący z Kraju Basków. Był również prawnikiem, historykiem i pisarzem.

Przypisy

Hiszpańscy malarze realizmu
Baskijscy artyści
Urodzeni w 1842
Zmarli w 1917

redpajama_set_name: RedPajamaWikipedia


Maybe you were thinking of not going to Disney or Universal because of a recent injury.
Now you can with one of our ECV's.
Couple of things to keep in mind when selecting a scooter.
First get a scooter that is in proportion to your weight.
Renting a standard scooter when you need a heavy duty one will speed and battery life.
Second if you are staying off property make sure scooter can be disassembled, reassembled easily and fit into the trunk of your car.
Ours will do be disassembled and reassembled in less than a minute with no tools needed.
The delivery driver (free delivery) will show you how this is done.
He won't leave till you've got the hang of it.
Our scooters are new or almost new.
Motors are never more than a year old.
In the very unlikely event you should have an issue with scooter, we will come out to the park no matter what time it is!
You can rent a scooter from us knowing we will look out for you from the moment we deliver scooter off till the moment we pick up the scooter.


text:
Options at AHS Open for Student Givers
Emma Janousek
Pictured above is the toy drive poster pinned up in the AHS commons. The Respect Club organized the book and toy drives to spread the giving spirit.
Emma Janousek, Staff Writer
This holiday season, Arlington High School has presented multiple opportunities for students to give to others. During this time of year, nearly everyone is focused on planning gifts for loved ones, friends, and family, but for those who look to give beyond themselves, AHS had several options. The giving opportunities this year included the food drive, the book drive, the toy drive, and DECA's Santa's Helpers.
The food drive, put on by ASB and Leadership, took place earlier this month and was successfully concluded, thanks to the giving spirit of the Arlington High School student body. DECA's work paid off as well, as many families this season will have food to make the holidays brighter.
ASB Public Relations Officer Riley Oakes ('16) explained, "It's important [to organize drives for giving] because of course not every student has the same opportunity as the peer next to them so providing these necessities and opportunities for students is a good trait for a school to have."
And his opinion seems to be shared with many of the students and staff at Arlington High School when the results of the drives are observed.
The book drive that ended last week closed successfully as the Respect Club reported that upwards of 2,239 books were donated, with the winning classes being Grabowski, donating 662 books, and Dailer, donating 446. The Respect Club is now planning to wrap books in sets ranging from preschool to middle school level. The sets will be delivered to the four elementary schools in Arlington and sent home with students as a part of the "Meals to Monday" program, in which food is sent home with students for over the weekend. Their families will receive books for the holidays due to the philanthropic students as AHS.
The Respect Club also organized this week's toy drive from December 14 through thursday the 17th. Ms. Strickland, teacher at AHS and adviser of the Respect Club, explained the idea for the project originated in her classes, and the toys were initially going to be given to children in hospitals around the area. However, although that was a good idea, Strickland stated that they agreed on focusing more on the Arlington community and its families. As it stands now, the donated toys will go to the elementary school counselors and will be given to underprivileged families for the holidays.
If making a family's holiday season wasn't enough incentive to donate, the Respect Club is advertising that with every toy a student donates, that student will receive his or her name placed in the raffle for a Red Robin gift card and two movie tickets; therefore, the more toys a student donates, the more times they will get their name placed in the drawing. The drive will end Thursday and will conclude AHS's giving spree for the holidays due to winter break.
"Obviously, it's important to the community and in the meeting of the necessities of the community," said Strickland. "The part that is most exciting however is that the drives were all student driven projects.We [The Respect Club] went from November to December embarking on this concept of 'Random Acts of Kindness,' which included all student designed, directed, and planned activities. It's important for the community, but as, if not more important, for our students to have opportunities to give."
With such a large amount of school-wide participation, it's a shame winter break has to cut our students' giving short. However, the amount of work the student body accomplished has left a stamp on the Arlington community.
Emma Janousek, Staff Writer/Photographer
Emma Janousek is a senior at Arlington High School. She is a member of National Honor Society and Link Crew. Emma also is a part of the cross country...
Looking for New Electives for Second Semester?
AHS To Host Another "Nerd Out"
AHS Leadership Announces Food Drive
What's on Your Plate?
Guardians of AHS


Simon Beames is Senior Lecturer in Outdoor Education at the University of Edinburgh. For 25 years, Simon has taught outdoors and indoors in North America, Asia, and Europe. He has published over 50 journal papers, book chapters, and magazine articles. Other books published by Simon include Understanding educational expeditions, Learning outside the classroom, Outdoor adventure and social theory, and Adventurous learning.
Chris Mackie is Associate Lecturer at the University of the Highlands and Islands' School of Adventure Studies in Fort William and a PhD researcher at the University of Edinburgh. Chris was literally born and raised at an outdoor adventure centre and now works across adventure education, tourism and outdoor learning.
Matthew Atencio is Associate Professor and Co-Director of the Center for Sport and Social Justice at California State University East Bay, USA. Matthew researches lifestyle/adventure sports and Physical/Outdoor Education. Matthew has contributed over 50 academic papers/chapters and a book: Moving boarders: Skateboarding and the changing landscape of urban youth sports.


Cater to your senses. Rejuvenate yourself with these body treatments.
The scent of lemongrass leads you to a healing and inner cleansing. This treatment will promote a clearer state of mind. Before beginning, your body will be dry brushed, prepping it for the treatment. This Hydrating body wrap will utilize warm oils on the body for extreme hydration. You will be cocooned/wrapped for 30 minutes while the therapist relaxes your mind with a coconut oil lemongrass infused scalp treatment ritual.
Body wraps are one of the most effective ways to lose inches fast while toning and firming the skin. Our Body Wrap Formulas work wonders by pulling toxins and impurities out of the skin, increasing circulation and thereby reducing fatty deposits and promoting inch loss. We use an herbal organic product on the skin. You will then be wrapped and placed in the infrared Sauna to maximize the potential to lose 4-20 inches total. This is great before a big event or PT Test (Military)-Pass your test! Measurements are done before and after session. Instructions for maintaining results until the event/PT test will be given. You can choose an area of the body for our target treatment session or the entire body which is recommend to maximize results.
Say goodbye to dull skin. This service will include a 40 min full body scrub with tropical exotic oils. The body scrub will be performed in dry room setting. You will be given disposable under garments for modesty. Before beginning with scrub, your body will be dry brushed, prepping it for the treatment. Your body will then be scrubbed revealing smooth skin.
Choose from your choice of Exotic oils: Noni, Pineapple, or Guava.
With this treatment we utilize eminence organic products. This service consists of dry brushing to prep the skin, absorption of the product to improve elasticity followed by applying the cinnamon paprika body lotion that assists in diminishing the appearance of cellulite. This product enriches the skin with essential vitamins and antioxidants.


Hiring and electrical contractor to function in your home can be very expensive. I'm going to share a few tips that will conserve you money. I'm sure a great deal of contractors will hate me for, but I'm heading to do it in any case. I just hope my boss don't see this!
The price of the package alone is about half the total installed cost. It tends to make feeling to either get a vendor to do the foundation work and tie-in with the house electrical system, or employ independent mechanical and house electrician.
Part of the problem people encounter is that as this is most most likely a 1-time motion in that you will most likely only at any time have to get it carried out once in a lifetime, it is tough to gather all 1 is intended to know so as to make the correct decision for you, and your house.
We are the HVAC specialists. We specialize in the set up of quality heating and cooling gear. From central air conditioning to warmth pump installations, you can always besides exceptional workmanship. As much as AC goes, we know what will suit your needs. Having issues with your thermostat? You guessed it, we take care of these too. We are also educated to function on humidifiers and air cleaners.
If your house has a crawl area either above or beneath, that's the very best situation situation. In that case, a brief segment of electrical conduit will be installed out of the base or leading of the panel and turn into the crawl area to carry the wire throughout to the garage. Worst case scenario, is when there is no access above or beneath the house. These are the most challenging.
Candidate Duncan Hunter agreed with the requirement of torture, as did Tom Tancredo, who expressed a desire for "24" torture expert Jack Bauer to handle the gory particulars. The crowd greeted every advocacy for torture with cheers, laughter and thunderous applause. John McCain, who may be presumed to know a little about the apply, protested towards it. Which satisfied with complete silence. Bloodthirsty group, these Republicans. Which may explain much more than a small about our newfound standing in the world.
As to the media reports of this atrocity, you may have seen some American troopers kicking down a few doors. Absolutely nothing more. Someday when you have small better to do, check out some of the tales about Fallujah from individuals who had been there. They're unbelievable and they're accurate. Many thanks to our "free" press, it was some thing small that by no means occurred. Ignorance, as they say, is bliss. This time however, it might arrive with a price.
Always thoroughly clean chandeliers with warm drinking water and mild soap. If your chandelier is missing parts you are in a position to go on-line or ask at a lamp store for replacements. Also inquire at the lamp store about insured electrical contractors who can place your chandelier for you.


text:
scottish enterprise
Future energy leaders programme seeks new applicants
Scottish Enterprise (SE) is seeking applicants for its next Future Industry Leaders Programme for the energy sector.
£16m subsea centre opened in East Kilbride
A new £16million subsea development centre has been opened in East Kilbride.
Scotland-Japan partnership invests £21m for next wave of subsea challenges
A partnership between Scotland and Japan will inject £21m into six projects designed to tackle the next wave of challenges in the subsea industry.
Sciencesoft receives £670k grant for oil and gas software
Glasgow-based Sciencesoft creates reservoir simulation software solutions and has been awarded £670,000 of SMART:SCOTLAND grants from Scottish Enterprise towards the development of new tools to support clients in the oil and gas industry.
Senior economist to help Aberdeen firms navigate Brexit
A senior economist at one of the world's biggest professional services firms will visit Aberdeen next week to help north-east firms navigate Brexit.
Scotland launches new £30m fund for low-carbon heating
A new £30 million fund for low-carbon heating infrastructure is now open for projects to make applications.
Economy expert to share knowledge at P&J breakfast event
A Scottish economy expert will share his thought on the future of the country's finances at the next Press and Journal Business Breakfast.
Cream of the crop in oil and gas rewarded
Exceptional oil and gas companies and their dedicated employees were recognised at one of the industry's most prestigious award ceremonies on Friday night.
Opportunities galore for graduates in energy transition, Scottish Enterprise says
The energy transition is dominating debate at the Offshore Europe 2019 conference in Aberdeen this week.
Energy is now the word on the streets of Aberdeen rather than oil
02/09/2019 by David Rennie, Scottish Enterprise
Once again Aberdeen and Scotland gear up to welcome the world for Offshore Europe.
'Waiting' energy sector urged to prepare now for Brexit
Firms in Scotland's energy sector have been urged to stop waiting and "prepare now" for the potential impact of Brexit.
Search for 'mix of grey and green' to create high-growth energy firms
The search is one for "a mix of grey and green" industry professionals to create new, highly-scalable businesses in the energy sector.
Get Brexit lowdown from experts at P&J breakfast
The UK economy has been under significant strain over the past year and, with an exit from the EU looming, seems unlikely to rally any time soon.
New Scottish offshore wind 'supply chain library' to be launched
A new Scottish "supply chain library" is set to be launched for offshore wind developers to identify firms for future projects.
£100K study launches to support Aberdeen's hydrogen ambitions
A £100,000 study has been launched to develop commercial supply of hydrogen power and fuel cell technologies in Aberdeen.
Hydrogen economy could insulate Scotland from volatile oil price
05/07/2019 by Dick Winchester
In the week or so before I sat down at my desk to write this column, four important and potentially linked events took place.
Gold Awards to celebrate all things innovative
The way the world consumes energy is changing. Electric vehicles, windfarms and drilling rigs all have a part to play in securing energy's future.
Oil and gas 'probably not top of list' for young people right now, Scottish Enterprise boss says
Scotland's oil and gas sector is "probably not top of the list" for young people considering future employment, according to a Scottish energy chief.
Subsea UK event to focus on financing growth ambitions
A Subsea UK event in Aberdeen next week is aimed at helping companies finance their growth ambitions.
Vision 2035 to play crucial role in energy transition, oil chiefs say
UK oil chiefs believe their "vision" for the future can play a crucial role in tackling one of the biggest challenges ever faced – the energy transition.
Scottish oilfield service sector diversification 'here to stay'
07/05/2019 by Mark Lammey in Houston
The Scottish oil and gas supply chain's diversification into other markets is "only going to continue" as the energy transition gathers momentum, a business leader has said.
World's largest turbine firm on the hunt for Scottish wind projects
The creators of the world's largest offshore wind turbine are on the hunt for new Scottish projects.
'Pace and purpose' needed for Scottish renewables supply chain boom, unions warn
A sense of "pace and purpose" is required to ensure Scotland doesn't miss out on a renewable energy supply chain boom, according to two trade unions ahead of a Holyrood committee roundtable meeting today.
Groups in pledge on energy transition
A group of Scotland-based economic development enterprises have vowed to play a major role in the energy transition.
Scottish Enterprise driving culture of data innovation
13/03/2019 by Julie Roberts, Digital Energy Lead, Scottish Enterprise
What springs to mind when you hear the word Data? If you are a child of the 80's like me, your first thought a couple of years ago may well have been the quirky little tech kid from one of the decades favourite movies, Goonies. A couple of years ago maybe, but there are few today that will not be aware of the intrinsic role that data plays in the digital economy agenda and the reshaping of the industries for which it represents the greatest value.


In the Mail & Guardian of September 27 2017, union leader Zwelinzima Vavi pleads for economic reform in the shape of a socialist state. "Only socialism will end poverty", the heading proclaims.
Millions of South Africans are poor.
Executive salaries are rising relative to those of the poor.
Unemployment has reached unprecedented levels.
The key driver of poverty is in fact unemployment.
Education is poor to non-existent, and a major cause of unemployment and poverty.
Most of this regression occurred under the stewardship of the ANC.
This has been characterised in particular by state capture and corruption by interests like the Guptas.
Now comes the rub. These problems are to be rectified, we are told, by "inclusive growth" achieved by "some sort of social compact between government, business and labour as the solution", all with a view to establishing a "socialist economy".
First of all, what is meant by a socialist economy?
You get the drift. The state will not only have to play a greater role in the economy, it will indeed have to own the economic means of production (or at least confiscate those for use by cooperatives), and will have to control the lion's share of spending in the economy.
Now here is the challenge, and that is to identify examples of such an economy in the real world, and then to determine how SA can possibly be reformed to such a model and thus eradicate poverty.
Today there are three candidates for title of a real, live socialist economy. And those are Cuba, North Korea and China.
Over the same period, China's per capita income in real terms increased by about 1500%, which, given its large population (over a billion), makes it the biggest economic improvement in a single country in the history of the world. It helped that China has some of the best schools in the world. All of this combined to lift some 800 000 people out of absolute poverty. The point is, of course, that this change was made possible by China moving away from a socialist economy, not towards it. Despite its reform process being incomplete, the significance lies in the relative degree that large parts of its economy are no longer socialist, in that the means of production are in the hands of private companies and people, and not the government like before 1980. So China proves the opposite to what Mr Vavi contends for.
Of the remaining examples, Cuba is the poster boy for the die-hard socialists in South Africa. It has very low wages and very limited choice of lifestyle and entertainment. As for happiness, in terms of the Life Satisfaction Index of Adrian White in 2006 it achieved 85th place out of 187 countries rated (below countries like East Timor, Tonga, Grenada and Namibia). In the recent edition of the Human Development Index it ranked 68th, below countries like Serbia, Antigua and Barbuda, Panama and Kazakhstan. It has for many years had to restrain emigration by force. Raul Castro has in recent years felt compelled to embark on cautious free-market reforms and even a China-style Special Economic Zone at Mariel Harbour.
But at least it maintained good education and healthcare. And that is not to be sneezed at.
What is more, pro-Cuban advocates make the fair point that the US has for years imposed trade sanctions on Cuba, resulting in severe restrictions on imports and exports. Who knows how well it would have done without those sanctions?
So Cuba deserves a second look. Assuming South Africans want to live like the Cubans do, how will we get from here to there?
Bear in mind that what Mr Vavi called for in his speech, is for reforming South Africa from a relatively free market (albeit a poor example of one) to a socialist state.
Has that worked in the real world? I thought I would try and identify those states in the EFW Index that in recent decades significantly moved from a relatively free-market position to a relatively state-controlled one, and determine how that went for them. The first interesting thing to note is that there are not many examples of countries that significantly reformed in a statist direction over the last number of decades. I could find only three. As a control I put in the three countries that went the furthest in the other way (i.e. towards freedom).
As for South Africa: Between 2000 and 2014 its rating declined from 7.09 to 6.77 (by 0.32) and it barely managed to keep pace with world average per capita growth.It is clear that the countries which "reformed" their systems away from a free-market economy, suffered in direct proportion to the degree of reform they underwent, and all fell behind the world average growth rate. The most drastic reform was in the case of Venezuela, which also suffered a decline of 48% measured against world per capita GDP. On the other hand the countries moving towards market freedom, on average improved their income ratio by 66.84%.
The point is simple: If South Africa were to reform its economic system to a socialist one, it would have to reduce its EFW rating at least as much as Venezuela, probably more – with similar results in all likelihood. It won't work.
But it gets worse. We are to achieve this, we are told, by means of a tripartite "social compact" between business, government and trade unions. We do not have the Cuban "luxury" of a dictatorship of the Communist Party. We have the little matter of democracy to contend with.
Note what is being asked here. Of businesses is expected that they should sign away the means of production that they have built up over years, and all their private property, to the state. It will be hard enough in our vastly diverse society to get centralised agreement on most reasonable proposals. This proposal will simply be rejected by business as unacceptable. Then what will happen? Confiscation by means of forcible nationalisation of all factories, farms, shops, businesses, banks, professional firms? Can't be, that is not a social compact.
But even if the reforms needed to bring about a wholesale nationalisation of assets could be achieved, surely then the privileged classes are likely to flee our shores in droves – even assuming they cannot take along their assets, those having been confiscated by the state?
And then? How, for example, will education be improved in the desired socialist state? Our education system has been socialist for years, and where has that got us? We already spend more on education than most countries as a percentage of GDP. How is the creation of a more statist set-up going to improve education?
And employment? Will the state just take money from taxpayers and create more public-service jobs?
It must be understand that Cuba's full employment does not come without a price. Cuban wages amount to about $15 per worker per month. That how low wages must be in order to employ all workers and maintain social benefits such as universal health care and education. One has to wonder how Mr Vavi's beloved trade unions would respond to a regime where their members are asked to take massive wage cuts in exchange for such benefits? Not to mention the national minimum wage of R3500. How will that feature in the new workers' paradise?
It can be expected that the trade unions will not be pleased to forego rising and minimum wages in such a new system.
To change South Africa to a socialist state will not happen through a social pact. But however it happens, how Mr Vavi and his socialist cohorts will do it without causing a catastrophe of Venezuelan proportions, is not clear.


text:
Revealed: the one holiday destination where the pound rode out the Brexit storm
Hugh Morris
Domestic flights are good value so how about a trip to Mendoza? - @ Pawel Opaska
The pound's travails over the last five years are no secret, with each dip since the EU referendum hitting the pockets of British holidaymakers.
In the spring of 2016, one pound earned around €1.30 and $1.47; it is now €1.17 and $1.29, but both have since offered much more stark comparisons, with sterling once at near parity with the euro.
The impact on traveller spending power has forced some to consider more closely the in-resort costs of their trip, and choose destinations accordingly: swapping Spain for Turkey, France for Greece, Italy for Egypt.
But some of the best havens for value are further afield.
According to research by currency analysts Equals, the nation to have consistently offered British holidaymakers bang for buck - considerably so - since the referendum is a 14-hour flight away.
Buenos Aires, the Argentinian capital Credit: istock
There has never been a better time to visit Argentina, says Equals, which has tracked the pound against the Argentinian peso since 2016, when a pound bought 20-odd pesos; it now buys 78.
Sterling is up 274 per cent on the peso compared to June 2016, the month of the referendum, the figures show, and has sustained similar levels since; compared to January 2017, the pound is up a huge 307 per cent. That means that UK travellers earn an additional £754 more in the local currency for every £1,000 exchanged.
"Now more than ever holidaymakers need to be aware of what the pound is doing," said Ian Strafford-Taylor, CEO of Equals.
"The good news is there are some destinations where the pound has managed to weather the Brexit storm, and these could be the places to visit if you want your holiday money to stretch further in 2020."
Chris Moss, Telegraph's Travel's Argentina expert, says there are ways to ensure Britons make the most of the currency savings.
"Hotels don't adjust much while holiday lets do," he said. "So AirBnb and similar are good options for getting power out of your pound."
He points out that some flats in the Palermo neighbourhood of Buenos Aires start from £20 a night, while a glance at the hotel rates provided on the Telegraph's page for the best hotels in the city still display costs into the hundreds per night.
Similarly, while the cost of international flights may not alter (though Argentina is now served by low-cost, long-haul operator, Norwegian, as well as British Airways), domestic flights, long-distance buses, public transport and locally booked excursions are all good value, Moss says.
"But the biggest benefits are perhaps in food and drink," he says. "A steak dinner in a posh parrilla like La Brigada can now be had for £20-£25 for two, with a decent wine. This would have cost twice that a few years ago.
"Argentina also makes its own bubbly and the weak peso makes such luxuries accessible, for now – because this period of sweet money (plata dulce in Spanish) for Britons won't last."
Moss said that packages or organised tours do not seem to be any cheaper.
Argentina is not alone in having offered good value to British holidaymakers in the last few years: neighbouring Brazil has seen sterling perform well, with the real down 83 per cent today compared to June 2016. Zambia, too, a popular safari destination, is an option, with the kwacha down 15 per cent.
Inspiration for your inbox
Sign up to Telegraph Travel's new weekly newsletter for the latest features, advice, competitions, exclusive deals and comment.
You can also follow us on Twitter, Facebook and Instagram.


text:
Home News Channels Health Roberta A. Pagon Receives Lifetime Award in Genetics from March of Dimes
Roberta A. Pagon Receives Lifetime Award in Genetics from March of Dimes
TAMPA, Fla., March 27 /PRNewswire-HISPANIC PR WIRE/ — The founder of a public database that helps doctors analyze the usefulness of genetic tests in making medical decisions is the 2009 recipient of the March of Dimes/Colonel Harland Sanders Award for lifetime achievement in the field of genetic sciences.
Roberta "Bonnie" Pagon, MD, professor of Pediatrics at the University of Washington School of Medicine in Seattle, developed the Web site genetests.org in 1992 and today is the principal investigator of this National Institutes of Health-funded program. Dr. Pagon has been a medical geneticist for more than 25 years and also is adjunct professor in the University's departments of ophthalmology and medicine. Her clinical work focuses on genetic eye diseases and syndrome delineation — reviewing the symptoms of patients who do not have a diagnosis to see if there might be a new disorder.
"Dr. Pagon is responsible for sharing critical information about the diagnosis and management of genetic diseases with physicians worldwide," said Michael Katz, MD, March of Dimes senior vice president of Research and Global Programs, who will present the award today to Dr. Pagon at the Annual Clinical Genetics Meeting of the American College of Medical Genetics held here. "She is a pioneer in the field of medical genetics, and the March of Dimes is pleased to honor her."
In its 15-year history, genetests.org has grown to become an important international resource for genetic testing information. The site promotes the appropriate use of genetic testing in patient treatment and personal decision-making. For her work on GeneTests, Dr. Pagon previously received the American Society of Human Genetics 2006 Education Award.
Dr. Pagon also is a consultant to the Regional Genetics Program of Washington State and an attending physician in the Children's Hospital and Regional Medical Center Genetics Clinic. She is a member of the board of directors of the American Board of Medical Genetics (ABMG) and a member of the Clinical Practice Committee of the American College of Medical Genetics (ACMG).
She is the review board coordinator for the Collaboration, Education, and Test Translation (CETT) Program, which promotes the collaborative development of new tests for rare genetic diseases for use by doctors and patients, and supports the collection and storage of genetic test results so they can be used to guide new research.
More information about Dr. Pagon's work can be found online at: http://depts.washington.edu/medgen/faculty/pagon.html.
The March of Dimes/Colonel Harland Sanders Award for Lifetime Achievement in the field of genetic sciences is given annually to an individual who has made a significant contribution to the genetic sciences.
The March of Dimes is the leading nonprofit organization for pregnancy and baby health. With chapters nationwide and its premier event, March for Babies(R), the March of Dimes works to improve the health of babies by preventing birth defects, premature birth and infant mortality. For the latest resources and information, visit marchofdimes.com or nacersano.org.
SOURCE March of Dimes
Previous articleVitamin D Deficiency Has Emerged as a Silent Epidemic
Next articleAd Industry Gets Shot of Adrenalina as Shop Mounts Expansion Plan


The Lenovo Z5 Pro comes with a slider design bearing 6.39-inch full-HD+ Super AMOLED screen at 1080x2340 pixels resolution and 19.5:9 aspect ratio. It is powered by an octa-core Qualcomm Snapdragon 710 processor clubbed with Adreno 616 GPU, 6GB of RAM, and 64GB/128GB storage. On the software side, the phone runs Android 8.1 Oreo-based ZUI 10. Concerning imaging, the Lenovo Z5 Pro boasts 16MP+24MP dual rear camera setup and 16MP+8MP dual front camera setup supporting Face Unlock. A 3,350mAh battery completes the package.
Lenovo Z5 Pro price in India is expected to be Rs. 17990. Z5 Pro launch is expected to be in March, 2019. The 64GB variant costs around Rs. 17990 and comes in Black colour.
The Lenovo Z5 Pro comes with dual camera setup for both front and rear cameras, which makes it an ideal pick for the ones who seek better camera performance. Additionally, the slider design gives it an edge over phones with standard design.
Unlike the other slider design phones, the Z5 Pro does not have a high-end SoC, even though Snapdragon 710 offers snappy performance, it does not match the flagship level of Snapdragon 845 that is found on Xiaomi Mi Mix 3 and Oppo Find X.
The phone comes integrated with a mechanical slider on top of the front panel housing front camera and other sensors. The slider design is the latest trend catching up with smartphones, Oppo launched the first smartphone with slider mechanism, dubbed Oppo Find X. The Lenovo Z5 Pro is a cheaper take on the slider design. It features a 6.39-inch full-HD+ Super AMOLED display bearing 1080x2340 pixels resolution, 19.5:9 aspect ratio, and Corning Gorilla Glass protection layer on top. Additionally, the phone also packs an optical In-display fingerprint sensor, which is embedded into the screen and illuminates when the user's fingertip touches the screen while capturing the reflection for biometric comparison with the registered fingerprint.
The Lenovo Z5 Pro is powered by an octa-core Qualcomm Snapdragon 710 SoC engineered with optimized AI power and performance. The chipset is ideal for dual camera features. It has multi-core Qualcomm Artificial Intelligence (AI) Engine to handle AI-assisted functions on the phone with ease. The chipset also includes the Snapdragon X15 modem that is claimed to download files quickly with improved Wi-Fi coverage that does not deter by walls or any other physical hindrances for signals. There is 6GB of RAM onboard with 64GB/128GB of storage, depending on the variant. In terms of software support, the Lenovo Z5 Pro runs Android 8.1 Oreo with ZUI 10 on top.
The mechanical slider on the Lenovo Z5 Pro houses the front camera along with other sensors. There is a 16MP+8MP dual front camera setup, wherein the secondary sensor is an IR sensor that enables the Face Unlock functionality. The front camera supports features such as beauty mode for capturing flawless selfies. There is a 16MP+24MP dual rear camera setup with dual f/1.8 aperture, placed on the back panel. The rear camera supports dual-tone LED flash, autofocus, AI scene recognition, PDAF, HDR, Super Night Scene mode, 4K video-recording, and 1080p videos at 120 fps. A 3,350mAh battery backs the Lenovo Z5 Pro with support for 18W fast charging. Connectivity options on the phone include 4G LTE, Wi-Fi 802.11 a/b/g/n/ac, USB Type-C, Bluetooth v5.0, GPS/ A-GPS, and NFC.
How is the processor performance of this phone?
It has a very bad processor. It's just a waste of your money.
It's a very good processor.
Which processor does it have?
Does it support PUBG HDR graphics game?
I want to purchase this item.


I'm always on the lookout for great cleaning supplies for the kitchen like Shaggies and Shrubbies. The story on these is pretty cool too which is what drew me to this great product. I actually got to meet the inventor of this which is where I first heard the story. Her grandma never threw anything away, and when she (the inventor) got married, the grandma took her chenille robes and cut them up into potholders. One day, the inventor was cleaning in her kitchen and took the potholder and to wipe the counters and found that it worked perfect!
I personally got to try out a Shrubbie. It's a shaggie on one side and a nylon net scrubbie on the other. I've used it on pretty much everything in the kitchen, and it works awesome. I was especially impressed on how it got off dried spaghetti sauce off my stove with very little elbow grease. I have yet to find a job in the kitchen that it can't do!
A product with a great story that works! Definitely go check it out!