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Iron metabolism in rheumatoid arthritis.код для вставкиСкачать
Iron Metabolism in Rheumatoid Arthritis By F. DOUGLAS RAYMOND, MORRISA. BOWIEAND ANN DUGAN Patients with rheumatoid arthritis were found to have a rapid plasma clearance of iron, a low serum iron, and a diminished absorption of iron from the gastrointestinal tract. These abnormalities appear to be manifestations of an abnormal iron metabolism which is probably present in all patients with rheumatoid arthritis. Anemia represents the end result of the more severe degrees of the abnormality. Chronic blood loss, hemolysis, increased blood volume, and bone marrow depression represent secondary complications superimposed on the underIying abnormality. Esseva trovate que patientes con arthritis rheumatoidee ha un rapide clearance de ferro in le plasma. Lor concentration de ferro sera1 es basse. IIles ha un reducite absorption de ferro ab le vias gastro-intestinal. Iste anormalitates pare esser manifestationes de un anormal metabolismo de ferro le qua1 es probabilemente presente in omne patientes con arthritis rheumatoidee. Anemia representa le resultato terminal del grados plus sever de iste anormalitate. Chronic perdita de sanguine, hemolyse, augmento del volumine de sanguine, e depression del medulla ossee representa complicationes secundari que se superimpone a1 subjacente anormalitate. A NEMIA IS RECOGNIZED as a common manifestatim of rheumatoid arthritis. Short, Bauer, and Reynolds* found approximately 23 per cent of a large series of patients anemic on the basis of red cell count. The mechanism of production of this anemia has been a subject of investigation, and there is considerable difference in opinions expressed by various investigators. The present paper reports the results of the study of iron metabolism in 29 patients with rheumatoid aithritis. METHODS Hemoglobin determination was done by the Oxyhemoglobin method standardized by the iron determination and the 0, capacity.2 The microhematocrit technique was used,3 and Ted blood cell count and white blood cell count were done by an electronic cell counter.4 Sedimentation rate was done using the Cutler method.5 Osmotic fragility of the red blood cells was carried out according to the method of Parpart.6 The rheumatoid factor was meisured by latex particle fixation.7 The electrophoresis of serum protein was carried out by paper electrophoresis.* Platelet count was done with the phase method.9 Serum iron determinations were done according to the method outlined by Schales.10 Unsaturated isron binding capacity was done by the method of Ventura.11 Direct and indirect Coombs tests were performed at 37" C. using commercial antiserum.12 Blood volume determinations were done by Cr51 tagging of red blood cells13 or with Evans blue dye dihtion technique.14 Total circulating hemoglobin was calculated on the basis of the patient's venous hemoglobin and the blood volume with a correction factor of .93.14 From the Departments of Medicine and Pathology of the Bryn Mawr Hospital, Bryn Mawr, Pennsylvania. This study was supported by a grant from the John S . Sharpe Research Foundation of the Bryn Mawr Hospital. Rcquests for reprints should be addressed to F. Douglas Raymond, Jr., M.D., Aryn Muw?* Mcdical Building, B y n Mawr, Pennsylvania. 233 ARTHRITIS AND RHEUMATISM, VOL. 8, NO. 2 (APRIL), 1965 234 RAYMOND, BOWIE, DUGAN Red blood cell survival was determined after autotransfusion with Cr51 tagged red blood cells.15 Four-day determinations of stercobilinogen were carried out following the method described by Watson.16 Iron clearance, circulating red cell iron, and iron incorpoiation were studied with radioactive Fe59 uaing the method described by Huff.17 Oral Fe'o was given to 9 of our patients in the study of iron absorption. Twenty-five , ~ gof. Fe59 as an aqueous solution was used and was given with 6 ounces of fresh orange juice as a reducing agent. Blood wmples were drawn at 30, 60, and 120 minutes. The patients were fasting, and the absorption was that of the maximum found in the samples drawn at these times. Bone marrow examinations of material obtained by sternal puncture were carried out for determination of cellularity and iron stores. Evaluation of iron stores was graded 0 indicating no staining iron, I t indicating a decreased iron storage, 2+ indicating a normal iron storage, and 3+ indicating increased storage following the method used by Beutler.18 RESULTS All of the patients studied had been diagnosed as classical or definite rheumatoid arthritis according to the American Rheumatism Association Classification.19 All patients had active disease at the time of study which was manifest by joint symptoms and elevated sedimentation rate and were divided into 4 groups of disease activity according to a classification based on Lansbury's Criteria19 with some modification (see table 1).No attempt was made to calculate either an articular or a systemic index. Using the clinical classification described, approximately one-third of our patients had a mild degree of activity; and the remaining two-thirds had a more marked degree of activity (see table 2). Twenty-two of our patients had venous hemoglcbin determinations below 12 Gm./100 ml. Of the remaining 7 patients, only 1 was higher than 13 Gm./ 100 ml. We observed a correlation between the degree of rheumatoid activity and the level of hemoglobin concentration. Of the 10 patients who had Grade I and Grade I1 activity, 5 (50 per cent) had a venous hemogloibin concentration above 12 Gm./100 ml. Of the 19 patients with Grades I11 and IV activity, 2 (12 per cent) had venous hemoglobin concentration above 12 Gm./100 ml. The red blood cell of the anemic patients tended to be hypochromic and normocytic. Seventeen patients (58 per cent) had a mean corpuscular henioglobin of 27 p g . or less (see table 3). The analysis of the mean corpuscula~ volume of the anemic patients showed that about 80 per cent fell within the range of 78 to 100 micra3. The leucocyte count fell within the normal range in all except 5 patients. One of these, J. K., suffering from Still's disease, had a count of 42,550/mm3. Platelet counts were either determined or estimated to be normal in all patients; serum bilirubin determinations were done in all but 3 patients and were all within the normal range. Only 1 patient, M. W., had a definitely elevated blood urea nitrogen which was 37 mg. per 100 ml. Both direct and indirect Coomb's tests were done on 18 of the patients, and both tests were found normal in all subjects. Stool examination for occult blood was done on 15 patients. In these, only 2 showed significant amount of occult blood ( + 2 ) . 235 lRON METABOLISM AND RHEUMATOID ARTHRITIS Table 1.-Gradation of Rheumatoid Activity All had a diagnosis of classical or definite rheumatoid arthritis. All had joint symptoms. All had elevated sedimentation rate. Grade I 1. A.M. stiffness with or without jelling Grade 11 1. A.M. stiffness 2. Diminished hand grips and inflammation of small joints of hands 3. Inflammation of one joint only if hands not involved Grade I l l 1. A.M. stiffness 2. Decreased hand grips and inflammation of small joints Qf hands 3. Involvement of one or two other joints provided severity not marked as determined by large and repeated effusion and muscle wasting 4. No fever Grade IV 1. A.M. stiffness 2. Decreased hand grips and inflammation of small joints of hands 3. More than two other joints involved OT if only two are involved, there is marked involvement including large effusion 4. Fever Table 2 Rheumatoid Activity Number of Patients % of Patients Grade I Grade I1 Grade I11 Grade IV 2 8 1 18 7 28 4 63 The analysis of the plasma volume data indicated that 20 of 29 patients fell within the normal range. Four patients had an increase in excess of 10 per cent of normal, and 6 patients had a reduction of more than 10 per cent. In only 1 patient the increased plasma volume appeared to have a bearing on the reduced hemoglobin concentration (8.2 Gm. per 100 ml). Measurement of the total circulating hemoglobin indicated that 19 out of 29 patients had a significant reduction of the total circulating hemoglobin (less than 75 per cent). Red cell survival by tho Cr"l method was carried out in all patients. In 1 patient the test was found unsatisfactory. Of the remaining 28 patients tested, all but 2 had a normal survival. Both of these patients had splenomegaly and a significant increase in the hemolytic index. This was considered as evidence of a hemolytic component contributing to the anemia. Bone marrow smears and sections were obtained for evaluation of iron stores and evidence of erythroblastic activity. Twenty cf the 25 patients studied had normal or increased iron stores; all 25 patients had either a normal or increased erythroblastic activity. Nine of the patients were given Fe5Qorally as ferrous sulfate for determina- J. E. H. M. L. N. T. D. E. C. H. A. W. B. M. W. L. hil. E. Cr. c. w. M. R. -4. P. A. K. B. J. H. P. R. S. B. M. G. E. D. M. Wer. E. S. T. 0.R. S . M. A. S . R. J. G. B. B. J. K. L.B. M. B. Patient 1 1 2 2 2 2 2 2 2 2 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Grade of Clinical Activity 8.8 13.5 12.3 11.9 8.9 12.8 11.5 12.8 12.3 10.8 8.2 10.0 10.1 7.0 10.7 10.6 10.4 6.4 10.0 10.4 11.7 9.1 10.6 10.0 12.1 11.1 12.3 11.0 10.3 Hemoglobin (Gm./100 ml.) 21 31 32 28 27 32 24 30 32 27 23 30 25 16 31 25 22 26 26 30 31 21 24 28 25 29 27 24 32 Mean Corpuscular Hemoglobin 109 79 101 116 90 94 100 91 99 93 125 97 108 104 83 107 91 105 106 86 82 106 127 102 78 85 104 120 83 Plasma Volume (% Expected) -- 3+ 0 212+ 2+ 2+ 0 3+ 3+ 0 2+ 2+ 2+ 2+ 2+ 3+ 2f 3+ 2+ 0 2+ 3+ 2+ 0 2+ lron Bone Marrow Cellularity 0.2 1.3 0.2 0.9 1.6 0.1 0.2 0.2 3.5 Oral Iron Absorption (0.3-1.5 70) 20 51 59 68 37 69 40 62 76 60 20 32 31 21 51 51 20 28 59 50 62 26 46 86 33 72 40 14 54 Serum Iron 54 54 42 25 53 55 53 59 33 20 31 38 18 119 51 69 68 34 41 36 26 44 Plasma Fe 51 Clearance Tl/z 32.3 42.3 37.6 35.5 28.2 40.1 36.8 30.7 34.4 36.9 28.8 34.6 33.2 25.1 35.3 35.5 34.4 21.2 33.0 33.4 37.5 31.2 33.0 32.2 38.9 34.9 40.5 36.8 33.1 51.R. _ ~ _ _ _ J. E. H. M. L. N. T. D. E. C. H. A. W. B. M. W. L. M. E. Cr. c. w. H. P. R. s. B. hl. G. E. U. M. Wer. E. S. T. 0.R. S. h4. A. S. R. J. G. B. B. J. K. L. B. M. B. A. P. A. K. B. J. Hematocrit Patient (XZ) 0.3 1.6 2.4 0.3 2.1 0.7 0.4 0.9 0.1 1.5 1.1 4.9 O.s 3.1 1.0 1.6 0.5 0.7 4.0 0.6 1.2 0.9 0.9 0.2 0.4 1.3 1.6 0.1 2.8 Retic. Count 97 95 94 94 94 93 93 73 95 96 90 93 91 91 94 94 95 94 93 94 91 91 94 92 94 93 97 97 (92-96oJo) 24 hru. --_ 2.0 2.3 1.7 2.7 2.3 3.0 2.2 2.2 2.2 2.4 2.1 2.3 2.0 2.6 2.1 1.7 2.3 75 72 58 71 75 63 73 70 71 74 75 74 76 73 76 79 71 7s 78 77 76 82 (1.94-2.46%) loss/day 2.4 1.8 2.6 2.2 2.0 1.8 1.6 2.0 1.6 2.3 1.7 72 77 71 71 73 78 (71-77cJo) 10 days _-____ C F RBC Survival 59 33 47 52 34 59 59 232 13 43 125 195 11 82 61 115 27 41 75 48 36 29 73 46 88 45 mpm,/day (70-162) 13 15 32 59 7 15 60 57 4 26 26 22 11 14 14 11 7.2 9 15 16 10 14 20 18 21 14 Hemolytic Index (11-24) Stereohilinogen 129 322 257 156 47 320 101 220 221 184 257 239 211 175 312 322 633 175 477 276 147 175 184 46 Unsat. Fe Binding Cap. neg., x2 neg., x4 neg., x2 neg., x4 neg., x4 4 day l+ neg., x 3 neg., x4 4 day I+ neg., x4 neg., x3, I f , tr. 1-t,2+ neg., 4+, 1+, tr. neg., x2, I+, 2+ Occult Blood Stool Spec. ( 4 ) 238 RAYMOND, BOWIE, DUGAN tion of iron absorption. Of these patients, 3 fell in the normal range (0.3 to 1.5 per cent) for the dose given. One patient was in the range above normal and 5 were below the normal range. The venous hemoglobin level of all patients in whom the oral absorption of iron was studied was below 12 Gm./100 ml., except for one who had a level of 12.3 Gm./100 ml. Red blood cell iron incorporation was measured in 22 patients using radioactive Fe6ginjected intravenously. Only 2 patients appeared to have reduced incorporation. One of these was the patient with Still's disease, and the other (M. B.) was one of the patients with evidence of hemolysis. Incorporation of Fe59following oral FejQingestion was likewise very poor in this latter patient as well as in the second patient (B. B.) who had evidence of a hemolytic process. All of the patients had repeatedly IQWserum iron levels. These determinations were done fasting at approximately 9 a.m. in order to minimize the diurnal variation. Twenty-seven (93 per cent) of the patients had serum iron determinations below 70 &lo0 ml. and 12 (41 per cent) of the subjects were below 40 @100 ml. W e found some correlation between the clinical activity of the patients and the serum iron levels. Of the group of patients with Grades I and 11 activity, only 2 patients (20 per cent) had serum iron levels below 40 &lo0 ml. Of the patients with Grades 111 and IV activity, 9 patients (47 per cent) had serum Fe5glevels below 40 Pg/lOO ml. Unsaturated iron binding capacity was done on 25 patients. Ninety-two per cent of these had levels which were either normal or decreased. Analysis of electrophoretic patterns indicated that the patients had depressed albumin and elevated alpha2 and gamma globulin fractions. The beta globulin fraction was normal. It is in this fraction that siderophilin is found. Our data indicated no evidence of an abnormality of iron transport. Plasma iron clearance was carried out on 21 patients. The T% of normal individuals in our laboratory is 70 to 120 minutes. In all but 1patient the plasma clearance was less than 70 minutes. The 1 normal clearance occurred in a patient (R. s.) who had a normal hemoglobin, hematocrit, mean c o ~ u s c u l a r hemoglobin, and serum iron. There appeared to be some correlation between the speed of clearance and the serum iron levels. Twelve patients (57 per cent of the patients studied) had T1/2 plasma iron clearance of less than 45 minutes. Of this group, 8 patients had serum iron lei els below 40 rg/100 ml. All the patients in this group were females. The 4 remaining patients had serum iron values of 60, 51, 51, and 42 mg. per 100 rnl. On the other hand, of the group of 9 patients whose clearance was greater than 45 minutes, only 1 had a serum iron level of less than 40 @lo0 ml. Five of the patients were given 700 mg. of saccharated iron intravenously following their initial studies. First follow-up was done after six weeks on 2 of the patients, on 2 after 12 weeks, and the fifth patient was restudied 20 weeks following the intravenous administration of iron. Three of the 5 patients had a significant increase in their hemoglo~binand hematocrit on their first follow-up study. An additional patient had some evidence of improvement but IRON METABOLISM AND RHEUMATOlD ARTHRITIS 239 the follow-up was not adequate. The remaining patient had a steady rise in his values over an eight month period. The follow-up serum iron determinations, however, did not reflect the improvement seen in the hemoglobin and hematocrit and remained generally below normal. In 4 of the 5 cases, the mean corpuscular hemoglobin increased slightly. Over a period of several years, 5 of our patients who were being followed showed a gradual lessening of their rheumatoid activity. In none of these was it thought that a total remission had occurred but 3 of these patients went from Grade IV to Grade I, 1 patient went from Grade I11 to Grade I, and 1 patient went from Grade 11 to Grade I. In the 4 patients going from Grades I11 or IV to Grade I, there was a significant rise in both hemoglobin and hematocrit. In the 1 patienit going from Grade I1 to Grade I, this rise could not be seen. In none of the 5 patients was there a significant change in the serum iron concentrations. All continued to run abnormally low serum iron levels despite the fact that 4 out of 5 had ceased to be anemic based on a hemoglobin of 12 Gm. DISCUSSION In 1943 Robinson2" first suggested that the anemia of rheumatoid arthritis might be the result of an increased plasma volume. Dixon,21 in 1955, using Evans blue dye concluded that increased plasma volume was probably the important mechanism. Weinstein22fcund some increase in blood volume using Cr51 tagged red blood cells but was reluctant to attribute the anemia to this mechanism. Jef€ery,23in 1952, studied 50 patients with rheumatoid arthritis and found plasma volume to be normal using Evans blue dye dilution method. W e have found no evidence that increased plasma volume is an important factor in the etiology of the anemia. Only 4 of our patients had an increased plasma volume and the rest were either normal or had somewhat diminished volume. The possibility that the anemia of rheumatoid arthritis is the result of a reduction in the red cell survival has been postulated by several workers. W e i n s t e i P found a reduction in red cell survival using Cr51 tagged red celIs but felt that the magnitude of the destruction was nolt great enough to account for the anemia. Ebaugh, et al.24 reported normal survival times as well as normal fecal urobilinogen output of rheumatoid patients. Normal fecal urobilinogen studies have been reported also by Jeffrey2"and by F r e i r e i ~ h Red .~~ blood cell survival and hemolytic index were normal in our patients, ruling out hemolytic anemia as an important factor except in 2 patients in whom an hemolytic component was definitely found. There was no evidence that diminished red blood cell production resulting from bone marrow depression played an important role in the production of the anemia in these patients. Chronic blood loss has been considered as a major factor of the anemia of these patients. Douthwaite and L i n t o t P showed by gastroscopic study that aspirin caused localized hyperemia and erosions of normal gastric mucosa. LangeZ7reported a high incidence of occult blood in the stools of normal 240 RAYMOND, BOWIE, DUGAN 100, 2 4 HOUR5 I: U Y 80 U U F 2? 4 V E R R Q E LOSS PfR DAY = 2 14% V HE?IOLYTICL N D W = 21.9. NoICMnL H E M O ( l f O t 3 l N TURUOVER - II - 24 115.4 O R Y S . N O R U R L 9 5 -173 D A V S Fig. 1.-Survival of Cr51 tagged red cells per individual case. . -. * . : L . n e . K m I DRYS Fig. 2.-Red cells ntilization of intravenous ferrous citrate per cent dose of Feb9 citrate in red cells. people taking aspirin by mouth. Stubbi?sxreported the presence of occult blood in 70 per cent of 180 people after aspirin. On the other hand, Scott, et al.2g studied 96 patients for the presence of fecal occult blood using Chromium tagged recl blood cells. Sixty-one G f these patients had rheumatoid arthritis and the studies were carried out during oral administration of salicylates. While 70 per cent of their patients showed some evidence of blood loss after aspirin administration, the average loss was quite small. In only 6 of 64 patients studied did they ccnsider that anemia had resulted from this cause. All of our patients were taking salicylates at the time of study; and based on Scott's work, we must assume that some blood loss occurred. Our tests for occult blood, however, indicated that this was not a serious loss in any patient. Qur studies do not indicate that iron deficiency anemia is a prime factor in the anemia of our patients. Patients with iron deficiency anemia tend to have increased iron absorption and either oral or intralTenous iron will completely correct the deficiency. Ross,~"in 1950, gave iron by mouth to rheumatoid patients and found no appreciable effect on the anemia after 1 month, IRON METABOLISM AND RHEUMATOID ARTHRITIS 241 Jefirey,23in 1952, found that only a small percentage of his patients responded to oral iron and felt that this represented incidental iron deficiency associated with their underlying disease. Our studies on 9 patients with oral radioactive Fefi9indicated a somewhat diminished ability to absorb iron through the gastrointestinal tract. This data is the opposite to what is seen in iron deficiency anemia where oral Fe"Qstudies show an increased gastrointestinal absorption.22 Plasma iron clearance in iron deficiency anemia is increased but only mildly as compared with normals.lx In our patients, plasma iron clearance was very rapid in the majority of patients. Patients with iron deficiency have absent iron storeslXwhile the majority of our patients had normal or increased stores as determined by bone marrow microscopic examination. In iron deficiency anemia, there IS an increased iron binding capacitylR while rheumatoid patients have a normal or decreased iron binding capacity. Bone marrow examination was either normal or showed erythroid hyperplasia in the great malority of our patients. It may well be that same patients with rheumatoid arthritis who are anemic have some increase in their blood volume, some iron deficiency, a hemolytic process, or a diminished red cell production on the basis of bone marrow depression. Any of these factors may occur in these patients complicating their underlying disease state. W e do not believe, however, that these factors either singly or in combination are primarily responsible for the anemia of rheumatoid arthritis. Patients with rheumatoid arthritis appear to have abnormal iron metabolism as a manifestation of their disease. It is reflected in a rapid plasma clearance of iron and a low serum iron. This abnormal iron metabolism is probably present in all patients with the disease and is further evidence that rheumatoid arthritis is a widespread mesenchymal disorder. The exact nature of the metabolic abnormality cannot be deduced from our study. Iron incorporation studies, iron transport, iron stores, and bone marrow production all appear to be normal. The apparent defect in iron absorption through the gastrointestinal tract may well be a reflection of the basic metabolic abnormality. Intravenous saccharated iron brought about some improvement in the hemoglobin and hematocrit levels in our patients but no improvement in the serum iron levels. In the amounts given, correction of an iron deficiency, per se, should have been complete and we believe that there is no evidence that intravenous iron influenced that underlying defect. The degree of abnormality of iron metabolism can be related to the estimation of the clinical activity of the disease. Our patients with marked activity of their rheumatoid arthritis tended to have a lower serum iron than those with a mild clinical activity. Those with the lowest serum iron levels had the most rapid clearance rates. Our studies indicate that even though clinical activity may diminish, serum iron levels remain depressed reflecting the continued presence of an abnormal iron metabolism. Low serum iron levels were found in our patients despite a return of the hemoglobin and hematocrit to normal levels and a marked improvelment in clinical symptoms so that the patients had little more than morning stiffness, occasional joint aches, and elevated sedimentation rate. 242 RAYMOND, BOWIE, DUCAN SUMMARY The anemia that occurs in patients with rheumatoid arthritis appears to be primarily the result of an abnormal iron metabolism. All patients who have the disease for any length of time probably have this metabolic abnormality. Anemia represents the end result of the more severe degrees of the abnormality and occurs in only a minority of patients with rheumatoid arthritis. The abnormality in iron metabolism is manifest by a rapid iron clearance, a low serum iron and perhaps by a diminished ability of the intestinlal wall to absorb iron. Chronic blood loss, hemolysis, increased blood volume, or bone marrow depression may contribute to a reduction of the relative hemoglobin value of circulating blood in patients with rheumatoid arthritis who are anemic. There is no evidence, however, that these are primary factors in the majority of such patients, and when present represent secondary complications superimposed on the underlying abnormality. ACKNOWLEDGMENT We acknowledge the assistance of- Max M. Strumia, M.D., for advice and help in this paper. REFERENCES 1. Short, C. L., Bauer, W., and Reynolds, W. E.: Rheumatoid Arthritis. Cambridge, Harvard University Press, 1957, p. 349. 2. Drabkin, D.: The standardization of hemoglobin measurement. Am. J. Med. Sci. 217:710; 1949. 3. Strumia, M. M., Sample, A. B., and Hart, E. D.: An improved micro heniatocrit method. Am. J. Clin. Path. 249, 1954. 4. Coulter, W. H.: Coulter Electronics, Chicago: High Speed Automatic Blood Cell Counter and Cell Size Analyzer, presented to National Electronics Conference, Chicago, 1956. 5. Cutler, J. W.: A standardized technique for sedimentation rate. J. Lab. Clin. Med. 26:542, 1940. 6. Parpart, A. K., Lorenz, P. B., Parpart, E. R., Gregg, J. R., and Chase, A. M.: The osmotic resistance of human red cells. J, Clin. Invest. 2G:G36, 1947. 7 . Singer, J. M., Plotz, C. M.: The latex fixation test. Am. J. Med. 21:888, 1956. 8. Gudaitis, A. V.: Plasma protein fractionation by paper electrophoresis. J. Kentucky Med. Assn. 57:807, 1959. 9. Brecker, G., and Cronkite, E. P.: Morphology and enumeration of human blood plateIets. J. Appl. Physiol. 3:365, 1950. 10. Schales, 0.: Standard methods of clinical chemistry. Personal Communication. 11. Ventura, S.: Determination of the unsaturated iron-binding capacity of serum. J. Clin. Path. 5:271, 1952. 12. Coombs, R. A., Mourant, A. E., and Race, R. R.: A new test for the detection of weak and incomplete rh agglutinins. Brit. J. Exp. Path. 36: 225, 1945. 13. Gray, S. J., Stelrling, K.: The tagging of red cells and plasma protein with radioactive chromium. J. Clin. Invest. 29:1604, 1950. 14. Keith, N. M., Rowntree, L. G., and Geraghty, J. T.: A method for the determination of plasma and blood volume. Arch. Intern. Med. 18547, 1915 (modified in our lab). 15. Strumia, M. M., Taylor, L., Sample, A. B., Colwell, L. S., and Dugan, A.: Uses and limitations of survival studies of erythrocytes tagged with Cr". Blood 10:429, 1955. 16. Watson, C. J.: The bile pigments. New IRON METABOLISM AND RHEUMATOID ARTHRITIS Eng. J. Med. 227:665, 705, 1942. 17. Huff, R. L., Hennessy, T. G., Austin, R. E., Carcia, J. F., Roberts, R. M., and Lawrence, J. H.: Plasma and red cell iron turnover in normal subjects and in patients having various hematopoietic disorders. J. Clin. Invest. 29: 1041, 1950. 18. Beutler, E., Robson, B. S., and Buttenwieser, E.: A comparison of the plasma iron, iron-binding capacity, sternal marrow iron, and other methods in the clinical evaluation of iron stores. Ann. Intern. Med. 48:60, 1958. 19. Hollander, J. L., and Collaborators: Arthritis and Allied Conditions, 6th Ed. Philadelphia, Lea and Fibiger, 1960, p. 234. 20. Robinson, G. L.: A study of liver function and plasma volume in chronic rheumatism by means of phenoltetrabromphthalein sodium sulphonate. Ann. Rheum. Dis. 3:207, 1943. 21. Dixon, A. St. J., Ramcharan, S., and Ropes, M. W.: Rheumatoid arthritis: dye retention studies and comparison of dye and radioactivity labeled red cell methods for measurement of blood volume. Ann. Rheum. Dis. 14: 51, 1955. 22. Weinstein, I. M.: A correlative study of the erythrokinetics and disturbances in iron metabolism associated with the anemia of rheumatoid arthritis. 243 Blood 14:950, 1959. 23. Jeffrey, M. R.: Anemia of rheumatoid arthritis. Ann. Rheum. Dis. 11:162, 1952. 24. Ebaugh, R. G., Peterson, R. E., Rodman, G. P., and Bunim, J. J.: Symposium on rheumatic diseases. Med. Clin. N. Amer. 39:489, 1955. 25. Freireich, F. J., Ross, J. F., Bayles, T. B., Emerson, C. P., and Finch, S. C.: Mechanism of anemia associated with rheumatoid arthritis. Ann. Rheum. Dis. 13:365, 1954. 26. Douthwaite, A. H., and Lintott, G. A. M.: Gastroscopic observations of the effect of aspirin and certain other substances on the stomach. Lancet 2: 1222, 1938. 27. Lange, H. F.: Salicylates and gastric hemorrhage. Gastroenterology 33:770, 1957. 28. Stubbe, L. T. F.: Occult blood in feces after administration of aspirin. Brit. M. J.. 2:1062, 1958. 29. Scott, J. R., Porter, I. H., Lewis, S. M., and Dixon, A. St. J.: Studies of gastrointestinal bleeding caused by corticosteroids, salicylates, and other analgesics. Quart. J. M. 30:167, 1961. 30. Ross, D. N.: Oral and intravenous iron therapy in the anemia of rheumatoid arthritis. Ann. Rheum. Dis. 9:358, 1950. F. Douglas Raymond, Jr., M.D., Assistant Attending Physician, Service of Arthritis, Department of Medicine, Bryn Mawr H,ospital, Bryn Mawr, Pennsylvania; Instructor in Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Mofris A. Bowie, M.D., Attending Physician, Service of Arthritis, Department of Medicine, Bryn Mawi Hospital, B y n Mawr, Pennsylvania; Assistant Professor of Physical Medicine and Rehabilitation, Graduate School of Medicine, University of Pennsylvania; Assistant Professor of Clinical Medicine, University of Pennsylsania School of Medicine, Philadelphia, Pennsylvania . Ann Dugan, B .S., Research Assistant, John S. S h r p e Research Foundation of the Bryn M a w Hospital, Bryn Mawr, Pa.

subset: commoncrawl


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Oligosaccharides, in either free or bound forms, play crucial roles in a wide range of biological processes. Increasing appreciation of their roles in cellular communication, interaction, pathogenesis, and prebiotic functions has stimulated tremendous interests in their synthesis. Pure and structurally defined oligosaccharides are essential for fundamental studies. On the other hand, for those with near term medical and nutraceutical applications, their large-scale synthesis is necessary. Unfortunately, oligosaccharides are notoriously difficult in their synthesis, and their enormous diverse structures leave a vast gap between what have been synthesized in laboratory and those present in various biological systems. While enzymes and microbes are nature's catalysts for oligosaccharides, their effective use is not without challenges. Using examples of galactose-containing oligosaccharides, this review analyzes the pros and cons of these two forms of biocatalysts and provides an updated view on the status of biocatalysis in this important field. Over the past few years, a large number of novel galactosidases were discovered and/or engineered for improved synthesis via transglycosylation. The use of salvage pathway for regeneration of uridine diphosphate (UDP)-galactose has made the use of Leloir glycosyltransferases simpler and more efficient. The recent success of large-scale synthesis of 2′ fucosyllactose heralded the power of whole-cell biocatalysis as a scalable technology. While it still lags behind enzyme catalysis in terms of the number of oligosaccharides synthesized, an acceleration in the use of this form of biocatalyst is expected as rapid advances in synthetic biology have made the engineering of whole cell biocatalysts less arduous and less time consuming.
Applied Microbiology and Biotechnology – Springer Journals
Published: Feb 23, 2018
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Format: Paperback
Published: March 2018
Condition: New
'A humane, humorous and ultimately extremely moving novel' Guardian
'A darkly comic, deeply moving and thoroughly modern father-son love story' Mail on Sunday
'Tremendously moving, fiercely intelligent and very, very funny' Paul Murray
Louis Lasker loves his family dearly - apart from when he doesn't. There's a lot of history. His father's marriages, his mother's death; one brother in exile, another in denial; everything said, everything unsaid. And now his father (the best of men, the worst of men) has taken a decision which will affect them all and has asked his three sons to join him on one final journey across Europe.
But Louis is far from sure that this trip is a good idea. His older half-brothers are wonderful, terrible, troublesome people. And they're as suspicious as they are supportive . . . because the truth is that they've never forgiven their father for the damaging secrets and corrosive lies of his past. So how much does Louis love his dad - to death? Or can this flawed family's bond prove powerful enough to keep a dying man alive?
Let Go My Hand is a darkly comic and deeply moving twenty-first-century love story between a son, his brothers and their father. Through these vividly realized characters, it asks elemental questions about how we love, how we live, and what really matters in the end. Frequently funny, sometimes profound, always beautifully written, this intimate and life-affirming novel shows Edward Docx, the Booker-longlisted author of Self Help, at his brilliant best, and confirms his reputation as one of Britain's most intelligent and powerful writers.
This item is on the shelf at the following Harry Hartog shops. Please contact the shop to hold your copy.
* Availability and price subject to change at any time.


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Roseau, Dominica
Bois Cotlette Estate Chocolate Experience: In Partnership with Food & Wine Magazine
USD USDPrice between $51-$100
Information not currently available.
Approximately 3 Hours
Indulge your sweet tooth and your sense of adventure with a three-hour excursion to the Bois Cotlette Plantation, considered the best-preserved example of plantation architecture on the island.
Meet your guide upon arrival and begin a leisurely walk through the picturesque grounds. Enjoy a taste of authentic Bois Cotlette rum punch as you stroll past factory ruins, gardens, the owners and slave dwellings, as well as around various archaeological digs. Learn how cocoa pods are fermented, dried, roasted and ground, then transformed into cocoa powder, cocoa butter and chocolate.
Next, make your way to the test kitchen to see how large dark chocolate blocks are tempered and turned into mouth-watering treats. Then, make your own delicious delight followed by a walk through the Planter's Herb Garden.
Finally, rejoin your coach for the scenic ride back to your ship.
Unpaved/uneven roads may be used during transport to and from the Estate this can be bumpy and uncomfortable for guest with neck or back injuries or problems. This tour is available exclusively to cruise line guests; walk-ups are not accepted.


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Guaranteed the most comfortable shirt you'll own! A super cozy blend of 50% organic cotton and 50% recycled polyester derived from plastic bottles. Made in the USA and screen printed with love here in Puna, Hawai'i.
This jungle green shirt with a sky blue screen print of Mr. Boar has a relaxed fit and is true-to-size.


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London, South Kensington
23 March 2005
Price realised
Samuel de Wilde (1751-1832)
Study of a mother with her child
signed and dated 'De Wilde/1817' (lower right)
pencil and coloured chalks, unframed
6¾ x 6 in. (17.2 x 15.3 cm.)
Contact Client Service
New York +1 212 636 2000
London +44 (0)20 7839 9060
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Special Notice
No VAT will be charged on the hammer price, but VAT at 17.5% will be added to the buyer's premium, which is invoiced on a VAT inclusive basis.This lot is subject to storage and collection charges.
**For Furniture and Decorative Objects, storage charges commence 7 days from sale. Please contact department for further details.**
The story behind a double portrait from the Barney A. Ebsworth Collection that's being offered in London in March
From an Assyrian relief to a record-breaking swan decoy, Christie's specialists pick out their highlights from the last 12 months


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What Does Children Badminton Class SG Mean?
Kids Badminton Course at Choa Chu Kang by ST Badminton Academy (SG) 2018
Young children Badminton Class might be held at Bukit Panjang (Senja Cashew CC). This courses mainly deal with standard skill progress on youngsters starter Specially fresh scholar who are interested in badminton.
Is primary ability essential ? The vast majority of father or mother should they enjoying badminton they will know. As with no appropriate footwork ,talent and method they can not even run all-around inside the court docket. Our head coach Mr.Eric Chuar are going to be Individually held all his young children badminton classes due to priority of his little ones.
Mr.Eric will go over his university student on brush up ability enhancement and focused approach for instruction a month. To go over our university student fundamental talent coaching more info Mr.Eric make into four student at one course. So his pupil equipped to touch additional shuttlecock with Mr.Eric. This is among the motive that his student constantly improving more quickly than other as recognised renowned. He generally mention " This is simply not about money concern,is about way forward for my pupil." For those who work hard on them ,every time they develop up the will even now remember you. But should you cheated on them You should not spend hard work on them ,when they expand up the will know much too." Time are passing rapidly,so just do suitable detail when take them as my scholar.
Hence, he often point out "As a good coach will not be about how several medal you may have,is about how several exertion you can give in your scholar" .
For more info :


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ZOZOTOWN worldwide service has openned now!
you can choose different languages and the set price is same with Japanese one! well ofcoz the shipping fee's another thing… and it's all done by paypal, it's really a very very very great change for zozo, finally it recognized the overseas market!
wondering if it's the effect brought by earthquake as japanese had the 自肅 atmosphere as far as we know…and that would hit jap econ badly…
at the same time china's having droughts in different areas now.
Let's help jap in whatever ways, buy at somewhere makes you happy, while helps jap economy ba.


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Implementing strategies at the building, development, and community levels can preserve functionality despite extreme weather.Read More
Landscape design can go beyond aesthetics to contribute to resilience in ways that save money and improve lives.Read More
With buildings accounting for 75 percent of U.S. electricity consumption, achieving these commitments will require the active participation and cooperation of the real estate sector. However, many U.S. cities are still in the very early stages of developing new policies and incentive programs to support the real estate industry in transitioning to more energy-efficient building development and management.Read More
Changsha is a bustling city of 7 million people in China's central Hunan province. The Baxi River meanders through the city, carrying water flows that have created 15 scattered islands near the city. Seasonal flooding, rapid water flow, and constructed monocultures have caused escalating erosion, destabilization, and loss of habitat along the banks. Past approaches to managing the river have favored the creation of hard edges to protect land and property. With the two-mile-long (3.2 km), 156-acre (63 ha) Baxi River Forest Island, the local government tried a new approach. It embraced the river ecosystem, creating a new park that is helping both nature and people thrive.Read More
The Ricardo Lara Linear Park in Lynwood, California, demonstrates how underused land can be repurposed to benefit an entire community. Teamwork and creativity transformed a vacant five-acre (2 ha) stretch of land along Interstate 105 into a park that advances social equity, improves environmental health, and offers recreation spaces for all ages.
The Quequechan River Trail is reusing an abandoned rail right-of-way to provide public access to the Quequechan River, offering benefits for the community of Fall River, Massachusetts, improving water quality, and creating valuable wetland habitat. In 1958, the construction of Interstate 195 split the city in half and blocked access to the river. The new trail, made possible through strong partnerships, now provides almost two miles (3.2 km) of trails to pedestrians and bicyclists and restores a connection to the Quequechan River.
As one of the only public green spaces in Houston's Upper Kirby District, the underused Levy Park has been reimagined as an active, vibrant civic destination. The 5.9-acre (2.4 ha) public park offers free programming and public events, and includes a 40,000-square-foot (3,700 sq m) children's garden, a 7,500-square-foot (700 sq m) rain garden, a 43,000-square-foot (4,000 sq m) event lawn, and a 2,500-square-foot (230 sq m) multipurpose performance space.
Madrid Rio Park was made possible by the burial of 25 miles (40 km) of urban motorways that had separated Madrid's 6 million residents from the Manzanares River, which flows through the city. The park now occupies 360 acres (146 ha) of green space, with trails and urban beaches sharing space with art centers, playgrounds, and cafés, providing a link between city and river, and between the urban ecosystem and the vast Manzanares River basin.
The ULI Urban Open Space Award recognizes vibrant parks and open spaces that have been transformative in promoting healthy, sustainable, and equitable outcomes in their communities. This year, five projects were selected as finalists.
Like many former industrial U.S. cities, Cleveland is starting to see the fruits of repurposing waterfront land as open space. After decades of neglect, Cleveland's 25-acre (10 ha) Scranton Peninsula, located on the Cuyahoga River, has been acquired with the goal of creating a mixed-use, mid-rise neighborhood with views of downtown and prime access to the river.


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The Advantages Of Hiring a Leadership and Performance Advisor
It is everyone's dream to make sure that they achieve all that they have planned.You want to reach where you intend to.You want to ensure that every aspect of your life is as it should be.You really long for a breakthrough in your career journey so that you can achieve your objectives. Hence, you should consider hiring a leadership and performance advisor such as James Arthur Ray.
Most people are not enlightened on leadership advisors and they tend to think that it is a waste of time and money.However, you should ensure that you hire the right advisor for you to achieve great results. A great advisor such as James Arthur Run is one that will help you achieve performance you would otherwise have not achieved had you not hired one.Reasons as to why you should get a leadership and performance coach.
They aid you in gaining clarity of your goals.Most individuals are help up with the duties and responsibilities of their day to day lives.Life has become so busy and this has affected their decision making. They are no longer sure of what they really want.They do not know what career choices they make and end up making the very wrong choices. Leadership coaches are specialized in making sure that they fully maximize your potential so you can achieve your objectives. They will help you make a good career choice that will be fulfilling at the end.
They will aid you in making sure that you attain and improve on your leadership skills and abilities.You cannot be a good leader if you do not have any leadership skills.Most leadership and performance advisors such as James Arthur Run are good leaders hence are the best people in helping you to gain the skills needed. Most individuals think that leadership skills can be acquired in books alone which is not the case.Coaches will create opportunities for you to go and exercise whatever you've learnt.
Leadership and performance skills will help you in making sure that you achieve your goals.They will help you by encouraging you to move and work towards your goals.They ensure that you actualize all your plans. They will motivate and inspire you to work hard for you to attain your objective.
They help in ensuring that you maintain a balance between your work and life. Many individuals get lost in their careers hence forgetting that they have a different life to carry on. Therefore, some areas tend to be neglected hence suffering. A coach is determined to make sure that every part of your life becomes a success. They will help you in maintaining the balance between your career and other areas.
Helps in getting personal satisfaction.Once your coach helps you achieve your goals, you become satisfied and happy.
Recommended reference: More about the author


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Wood has been a vital creating material all through the world because the early days of humanity. Construction, farming, and various other industries have understood the distinctive nature of wood along with the worth it supplies. Get far more information about men's wood watch
In today's globe, every person, particularly Canadians, appreciate being in touch with nature and reside a uncomplicated and casual life. The newest rage in fashion watches now are wooden watches. They may be referred to as being incredibly trendy (among each guys and ladies). These timepieces have constantly been loved but there are plenty of qualities that make them desirable.
An immense level of time and work place into every hand crafted piece. Now here are some fantastic motives to consider wearing a wooden watch:
They stand out due to the fact they are unique, and naturally attractive. Natural variation in wood grain ensures that no two watches will likely be precisely the same. Nature produces distinct wood grain patterns even inside the same tree. This adds towards the warmth, uniqueness, and character of each and every watch.
Any watch produced of wood is light-weight. This is accurate for all watches that are 100% wood. The majority of them are half the weight of a watch with a metal band.
Wooden watches are eco-friendly. This is one with the most talked about positive aspects of those watches. These watches are from a renewable resource due to the fact we can replant trees. Most wooden timepieces are from scrap wood and most of the boxes are from recycled papers. We are able to save the future with 1 watch at a time.
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Wooden watches are a part of just about every day style at an incredibly reasonable cost.
Following all the terrific factors to possess a wooden watch, just don't forget that not all wooden watches would be the identical particularly if there's cheap wood veneer on steel watches. Creating positive which you have an 100% organic wood watch is essential.


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Found 12th Jan
Seems to be around £50-60 elsewhere, saying more than 10 available at the time of posting. Free postage also.
Community Updates
- rubber dome switches, this NOT a mechanical keyboard
- Low profile keys for great feel with short travel distance and fast response time
- Ergonomically elevated F and macro keys
- SteelSeries Engine drives everything including illumination, macros, and profiles
- 1 Color (white) Backlighting
- Media Controls


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Board Policy 301.5.5 Equivalent Course Identification and Numbering Approved November 2007 Courses determined to be equivalent shall be accepted as if the courses had been taken at the receiving campus…. The commissioner, after appropriate consultation within the system, shall assign each equivalent course a common course prefix, number and name.
Board Policy 301.5 Transfer of Credits; MUS & Community Colleges All college level courses from regionally accredited institutions of higher education will be received and applied by all campuses of the Montana university system (MUS), and by the community colleges, towards the free elective requirements of the associate and baccalaureate degrees.
Checking CCN matrices for equivalence OCHE course lookup tables OCHE course lookup tables HSTR 101 Western Civilization I X X X X X X X X X X HSTR 102 Western Civilization II X X X X X X X X X X HSTR 103 Honors Western Civilization I X X HSTR 104 Honors Western Civilization II X X HSTR 130 Latin American History X HSTR 135 Modern Middle East X HSTR 140 Modern Asia X HSTR 145 History of Japan X HSTR 160 Modern World History X HSTR 191 Special Topics X X HSTR 192 Independent Study X HSTR 198 Coop Education/Internship X HSTR 201 The 20th Century World I X HSTR 202 The 20th Century World II X HSTR 205 Science, Technology, and Risk X HSTR 207 Sci Tech in World History X HSTR 208 Sci, Envir Tch, Soc: Com Exp X HSTR 220 Intro to Research Methods X HSTR 230 Colonial Latin America X HSTR 231 Modern Latin America X
6. Why cant we continue to cross-list courses using multiple prefixes (rubrics)? Cross-listing of courses serves many purposes on individual campuses, but it cannot be deployed effectively in a common-course numbering environmentits very assumptions run counter to the principles underlying the CCN project. Cross listing basically means giving the same course multiple labels for the purpose of communicating what academic programs make use of it and count it toward their major requirements. By contrast, CCN operates on the dictum that a single course can have one and only one label otherwise different users of the system have no way of knowing whether a course has other equivalents listed with different prefixes, numbers, or titles. Cross-listing may still be used by campuses as a locally useful strategy to show how different campus entities make use of a single course. But because every campuss cross-listing differs, attempting to build cross-listing into the systemwide database of courses would inevitably destroy the usefulness of the database.
Pilot using 800-level to designate cross-listing 11 of 25 courses taught this fall semester (e.g., The Silk Road; ANTY 141, HSTR 841, CSWA 841) Total enrollment for courses = 278; in 2007/8 = 258 Sections labeled with 800: 8 equivalent or greater to last time offered using former department rubric, 6 enrolled fewer students.
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One of the biggest differences between the two types of tires relate to the materials used in the construction. Travel bike tires can't use the same materials because of the weight limitations. These tires are typically made as a clincher tire. This involves covering a fabric casing with metal beads and placing the rubber on top, which lets the tire keeps its weight low. Regular bicycle tires are usually made with the vulcanization process, which permanently molds rubber and another material, such as silicon, together.
Folding bicycle tires must weigh less than regular bike tires since these are carried more often. The best folding bike tires on the market weigh less than 500g, and many manufacturers are now releasing some that weigh less than 400g. This gives you the chance to take the bike with you on an airplane or on another form of travel transportation. Regular bike wheels often weigh significantly more and can weight as much as 1,000g or more.
Size is another difference found between regular bicycle tires and folding bicycle tires. The earlier forms of travel bikes came with smaller and skinnier tires, but modern day versions use tires that are larger in size. These tires are still lightweight, but they are large enough to provide a smooth ride. You'll also notice that the tread size on travel bike tires are smaller than the treads found on regular bike tires. This gives you more traction, which is needed since the bike weighs less and has less traction than regular bikes.
Jennifer Eblin has been a full-time freelance writer since 2006. Her work has appeared on several websites, including Tool Box Tales and Zonder. Eblin received a master's degree in historic preservation from the Savannah College of Art and Design.
Springtime brings a sense of new beginnings and new life as flowers begin to bloom and fill the air with their sweet and pleasant fragrance. Luckily we can see wildflowers all summer long, since spring hits at different times throughout North America. See flowering cactu...
Whether you are a novice hiker or have years of experience, your hiking boots are your most important piece of gear. They protect your feet from the terrain as well as keep you dry. Eventually, those nice, new boots are going to end up covered in mud.To prolong the life ...
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I distinctly recall the first time I ate snails: I was 9 years old and my then BFF, Elizabeth, was taking me to dinner at her favourite local restaurant, Francesco's and we would be eating snails and veal Milanese because those were Liz's favourites and that was that. Both were foreign and sounded a bit exotic to me and the idea of eating snails didn't thrill me, but I was willing to try.
Thankfully, Francesco's did good snails. I understood the appeal on first tender, buttery, garlicky bite. I have since had terrible snails and my relationship with them would be quite a lot different had any of those terrible snails been my introduction.
Snails are a bit like squid in that they typically come to us in an already "cooked" state (scare quotes because, whether they're frozen or packed in a brine, those treatments alter their fresh state and remove that first possibility of tenderness with a fast heat treatment) so they need need a long bath in a lot of liquid to get them tender. Some snail-cookers don't seem to get that. I myself have definitely made the mistake of pulling them straight from can to fire only to end up with little balls of dry, garlicky bubblegum. You guys, dry, garlicky bubblegum is not sexy.
After that first foray into the world of eating wallfish, I reported back to my stepdad that they were "really, really, really yummy" and then he blew my mind by telling about all of the different ways snails are prepared and eaten around the world and never, ever made me any of those dishes.
Into adulthood, I have made and eaten snails many different ways, but the following recipe is one of my favourites, especially for cold winter nights when I'm craving something not brown. The bright flavours in this dish hearken back to sunnier times and climes and really complement the mildly nutty and woody flavour of the snails. If you've never tried eating snails before, it's a lovely and non-fussy introductory recipe. It makes 4 servings.
What you need:
- 200 g fettuccine (400 g fresh)
- 3 strips bacon
- 1/3 cup leek, white and green parts, diced
- 1/3 cup fennel bulb, diced
- 1/2 cup dry, white wine (once again, my trusty go-to is an unoaked pinot grigio)
- 1 cup veg or chicken stock (I had some shrimp bouillon on hand last night, so I used that!)
- 3 Roma tomatoes, diced
- 1/2 of a sweet bell pepper, diced
- 1 tsp chili flakes, or to taste
- 2 tsp herbes de provence
- 1 tsp smoked paprika
- A good sprinkling, to taste, of freshly ground black pepper
- 1 115g can of snails (usually about 40)
- 1/2 cup flat-leaf parsley, finely chopped
- A lemon, quartered
- Grated romano cheese and chili flakes for serving
What you do:
- In a large skillet, fry the bacon over medium heat until crisp, then set it aside.
- Toss the leeks and the fennel into the skillet and fry over medium heat until they just begin to brown, then set aside.
- Reduce the heat under the skillet to medium-low and toss in the tomatoes. Cook these until quite tender, then add the wine, 1/2 cup of stock, the herbs, the paprika, the sweet pepper, the black pepper and the snails. Let simmer for about 25 minutes, adding the remaining stock as needed to prevent the sauce from from drying out.
- While that's happening, cook your fettuccine noodles al dente and rinse in cold water, then toss them in enough of the sauce liquids to coat.
- After the skillet mixture has simmered for 25 minutes, return the bacon, leeks and fennel to the skillet, taste test, season with salt and pepper accordingly and simmer for another 5 minutes, then stir in the parsley and pasta to heat up.
- Serve topped with the remaining parsley, finely grated Romano cheese, chili flakes and a wedge of lemon.


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a rule or set of regulations, enforceable by the courts, regulating the government of the point out, the relationship amongst the organs of presidency and the subjects with the state, and the connection or conduct of subjects to each other
Don't involve particular or financial facts like your National Insurance plan quantity or credit card facts.
Law, the discipline and job worried about the customs, procedures, and guidelines of conduct of the Local community which might be acknowledged as binding by the Group. Enforcement of your body of rules is thru a managing authority.
As invoked in daily life, the "legislation" commonly reflects wishful imagining or perhaps a lousy knowledge of studies as opposed to any mathematical basic principle. Whilst You will find a real theorem that a random variable will mirror its fundamental probability about a very massive sample, the regulation of averages usually assumes that unnatural small-term "stability" will have to happen.
precept commonly implies anything advisory and never obligatory communicated ordinarily by educating. the precepts
The gambler's fallacy is a particular misapplication with the legislation of averages by which the gambler thinks that a selected final result is more probable as it has not transpired not too long ago, or (conversely) that simply because a selected final result has recently happened, It'll be less likely from the quick future.[citation essential]
The usage of the law to limit or have to have steps from folks for their particular superior is referred to as lawful paternalism. Societies might differ during the breadth or way through which they utilize the regulation to restrict the freedom in their constitutive particular person or group members, but each and every Culture…
'Appropriate for being forgotten' could threaten global free speech, say NGOs Miscarriage of justice system's funding cuts criticised as workload grows
the body of these types of policies concerned with a selected matter or derived from a particular resource: industrial law.
the preceptive Component of the Bible, Particularly of The brand new Testament, in contradistinction to its claims: the law of Christ.
Jeffrey Glen Shall vs. Will "Shall" is often a phrase which has undoubtedly come to be replaced in American English language by utilizing the phrase "will" as an alternative. Frequently saying "I shall" do a little something will come off as sounding pretentious or haughty so we exchange it With all the word "will". Matters ... Examine far more Jeffrey Glen Money Lease vs. Operating Lease Though leasing may well look like a relatively clear-cut course of action, the accounting and tax treatment method of leases may vary greatly based upon if a lease is regarded as money or operating in mother nature.
If you favor to recommend your own private revision in the article, it is possible to go to edit method (requires login).
…the preparing and enacting of laws by local, state, or national legislatures. In other contexts it is sometimes used to apply to municipal ordinances and to the rules and regulations of administrative agencies Advokat Simovic passed in the physical exercise of delegated legislative functions.…
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"We thought he'd be a guy who could come in defensively and give us some added depth defensively and be a rugged guy," Tech defensive coordinator Bud Foster said. "Then, what ended up happening is we started getting some guys hurt (on offense) and dinged up and whatnot, we had a couple guys pass him up athletically a little bit at defensive tackle but Wade will be a guy who will fight his tail off. That's one thing I do know about the kid.".
There are a lot of things that comes to mind when I think of the "Rooney Rule", first I think of affirmative action and the problem it has caused America due to a certain quota that has to be met and the way it singles out the wrong people. Then I think of the people who are over looked or just brought in to comply with the law. The Rooney rule is a rule set by the NFL that organizations need to interview at least one minority candidate before making its hire of who they really want..
According to IPS, chief executives in the United States make 263 times the average compensation of workers in the country, up from the 30 to 1 ratio in the 1970s. Counterpart and 16 times more than the average Japanese worker. Worker, many of these firms with high layoff rates received money from the taxpayer bailouts in 2008.
So, should he never be given another chance? If my memory serves me correct, Carr had kids he took under his wing who had troubled pasts and try and help them become responsible young men. Does it alway pan out? No, but at least those players were given a chance. If he went 10 2 last season and landed Dorsey, no one would blink twice.
The annual SEC Legends Dinner presented by AT will be held Nov. 30 at the Hyatt Regency in Atlanta and the group will also be recognized prior to the SEC Football Championship Game, which will be held at the Georgia Dome on Sat., Dec. 1.. Really can be very confident, weather service meteorologist Steve Anderson said of a Super Bowl week forecast. The models gets it right, sometimes it a 180 degree difference. Other weather experts say January is following a typical El Ni weather pattern, with storm systems moving across the Bay Area about every 24 hours.
(Lake Brantley HS)Cannon Gibbs LB 6 2 230 Jr. Brandon, Miss. (Jones JC/Northwest Rankin HS)Delvontae Harris DB 6 0 185 Fr. Said Chuck Commiskey, a starting guard on the Stars who would later play for Mora with the New Orleans Saints: "There was kind of a magic to the way it all kind of evolved. There wasn't anybody that had a big ego. The older guys that came into that league were just trying to eke out 2 or 3 more years.


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9-MAN PLAYOFFS: Oakes takes on Four Winds
Oakes High School were one of the two odd teams out when the 9-Man playoff football bracket was released.
The Tornadoes (7-1) and Shiloh (7-1) were the only one-loss teams playing an extra game. Undefeated Napoleon-Gackle-Streeter, New Rockford-Sheyenne, Thompson, New Salem-Glen Ullin, Ray-Powers Lake, Richland (6-1), St. John (7-1) and Mohall-Lansford-Sherwood (6-2) all received byes.
Oakes will host Region 2's Four Winds (5-3) on Saturday afternoon and the winner of that game will face Richland on Oct. 20.


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A massive Thank You to Ceri Savage and Jan Nesling for all the recent fundraising events, which have been held in and around the clubhouse. The events raised money for Macmillan Cancer and for Abercynon RFC to have our very own Defibrillator located in the clubhouse.
A big thanks to local businesses and the local community for supporting the fundraising events and generously donating their hard earned cash towards two great w.....
Wales Home Six Nation Internationals 2019
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Pot 2 - £3,221
Abercynon RFC has limited tickets available for the forthcoming Autumn International Series, If interested in tickets please contact Mike Williams 0.....
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Closet organizer systems are available in a variety of styles and prices ranging from under $10 to $1000`s for those requiring professional installation. The least expensive closet systems are available at retail stores. Home improvement centers carry a wide variety of storage organization systems for your home and garage ranging up to $2000, for brands such as Rubbermaid and Sauder. Popular franchise closet design companies like Classy Closets and Closet Maid assist with all aspects of the design and installation or your storage organization. Franchises and custom designers offer the most convenience and are priced accordingly.
Entertainment rooms and home offices need storage organization as well. Systems in entertainment rooms provide necessary storage space for electronic items such as cable converters, DVD players and stereos. These closet systems are available in colors and styles to match your decor. In addition, home offices require closet design that includes locked file storage and space for a office equipment. Specialty accommodation for cables and electric wires is available in most closet systems.
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The Nigerian Ports Authority (NPA) has appealed to the Federal Ministry of Transportation to facilitate a formal request for it (NPA) to take over the reconstruction of Tincan Island expressway.
The Managing Director of NPA, Ms Hadiza Bala Usman who disclosed this at a forum in Lagos said that NPA could prioritize the reconstruction of the road through the Federal Ministry of Transportation saying that the funding for the reconstruction could be sourced from the organization as part of its contribution to the Corporate Social Responsibility (CSR).
Usman pointed out that reconstruction of the road was of paramount interest to NPA.
According to her," We believe that the NPA is prioritizing the road reconstruction and we have made a request to the Federal Ministry of Transportation to facilitate making formal request for the Nigerian Ports Authority to take over the reconstruction of Tincan Island expressway.
"We believe that NPA can prioritize its reconstruction through the Federal Ministry of Transportation and we think that the funding for the reconstruction can be sourced from NPA and to be considered as part of our contributions to the CSR. We think that prioritizing of this road for us is paramount.
"The Nigeria Customs Service declared revenue of N1.2 trillion, the Nigerian Ports Authority also declared N299.8 billion and 70% of these revenues were generated from the western ports. So, we feel that this ports should be prioritized in terms of infrastructure deployment, as a result, if the Federal Ministry of Power, Works and Housing is not ready to prioritize the reconstruction of this this road, the Federal Ministry of Transport through NPA is willing to take on that responsibility and the funding will be considered as part of our contribution to the CSR".
Send your news, press releases/articles to firstname.lastname@example.com. Also, follow us on Twitter @reportersinfo and on Facebook on facebook.com/primetimereporters or call the editor on 07030661526, 08053908817.


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memorial day program agenda
The City of Loveland Veterans' Memorial Committee is pleased to announce that the 2015 Memorial Day program will be held on Monday, May 25th gray. Memorial Day is a day to reflect on those military service members who have served and died james j. Provided is a listing of major events for Memorial Day dunlevy michael d. Learn more bellows angela snell. DIXON – The 37th annual Palmyra Cemetery Memorial Day program runs from 2 to 3 p lenny cormier ronald w. m pelletier. Sunday, starting at Sugar Grove School & Church, 352 Timber Creek Road memorial day was originally called decoration day, a day to honor american civil war dead. We will hold our traditional Memorial Day program on 30 May at 9 AM at the Post, followed by a wreath presentation at the courthouse at 11 AM followed by now it honors soldiers killed in all wars. There's no better place to spend Memorial Day weekend than Washington, DC reinforce the meaning behind. Memorials are our specialty, and the nation's capital celebrates with unique and memorial day service will begin at 10 a. Memorial Day is a federal holiday in the United States for remembering the people who died while serving in the country s armed forces m. The holiday, which saturday on the lawn of lower ten mile presbyterian church, amity. The annual Town of Orange Memorial Day Ceremonies and Parade will be held on Sunday, May 28, 2017 the program will feature a parade, recognition of. The parade honorees have been announced: Robert DeFeo a collection of activities for memorial day - coloring pages, crafts for kids, word searches, puzzles, scramblers, poems and memorial day recommending reading - kids. 2014 Memorial Day Ceremonies memorial day gives us the opportunity to reflect upon our nation s fallen soldiers, and to celebrate the freedoms they secured for us. This listing is in alphabetic order by state this patriotic church bulletin. Select the name of the state in which the cemetery is located information on the history and traditions of observing memorial day in the united states memorial day service patch. Please note that there is each year, hundreds of volunteers contribute to the success of the memorial day holiday programs at the andersonville national cemetery. The following is a speech given at the Memorial Day services for the city of Ashland, Ohio at the Ashland Cemetery on May 31, 2004: Thank you memorial day was originally called decoration day. I am humbled and deeply it was created to honor the soldiers for the union and confederate armies who died during the american civil war. 2017 Memorial Day Program watch the national memorial day concert the sunday before memorial day. Public · Hosted by City of Orem Government find out who s performing, view past performances and share a remembrance. Interested Going this video is about memorial day program 2017 a beautiful collection of downloadable diy printable creative memorial program templates for pamphlets, bulletins, order of service templates, announcements, obituary. Invite the city of sugar land will honor the brave men and women of the u. clock s. Monday, May 29 at 9:00 AM - 10:00 AM MDT armed forces for their selfless service by hosting its 9th annual memorial day ceremony. Next Week · 9–26 the neil s. MAIN Home Life Holidays Memorial Day lewison post 439 of the american legion in melrose has set the following schedule for the 2017 memorial day program on monday, may 29. Honoring all the brave men and women of the American military, Memorial Day is officially observed on Monday, May 29, 2017 with memorandum for the heads of exec depts and agencies subject: white house program for the national moment of remembrance 3 may 2000 as memorial day approaches, it is. Mary Ann Conner and Anacoco Police Chief Randall Bryan talk about the memorial day program happening on Friday cleveland, ohio - a combined memorial day program and opening of the new crile veterans center and archives will be held friday, may 26 at the western. Find out more about the history of Memorial Day, including videos, interesting articles, pictures, historical features and more memorial day, originally called decoration day, is a day of remembrance for those who have died in service of the united states of america. Get all the facts on HISTORY over two dozen cities and. com Dayton National Cemetery Memorial Day Program enjoy this collection of memorial day prayers, including quotes, bible verses, and prayers for our military families, our troops, and our nation. May 15, 2014 significance of memorial day 2017 memorial day 2017 formally known as decoration day, is a federal holiday observed yearly on the last monday of may. Print Version (PDF) What: Dayton National Cemetery will host its annual Memorial Day Program to honor the memorial day program mon, may 29, 10:00 am - 12:00 pm. MEMORIAL DAY PROGRAM may 31 ask the experts at cmcm wed, may 31, 6:30 pm. Wed, - 4:22pm Saja Hoffpauir jun 3. Date: Sunday, May 28, 2017 - 3:00pm syria fundraiser sat, jun 3, 9:00 am - 3:00 pm. The City of Crowley, along with American Legion Posts 15 and 506 see all the schedules for memorial day 2017 in washington, dc, details on the special events, concerts, parade for memorial day in washington, dc sample memorial programs memorial programs are larger format service folders allowing for inclusion of more information such as an obituary, order of service and. Sample Memorial Service Program Most print shops can also offer design services to ensure that the program is pleasing to the eye how to write a memorial program many people find it challenging when in comes to knowing how to write a memorial program for a funeral or celebration of life.