Blood Pressure Control and Antihypertensive Treatment among Hemodialysis Patients-Retrospective Single Center Experience.

Background and Objectives: Hypertension affects at least 80% of hemodialysis patients. Inappropriate control of blood pressure is mentioned as one of the essential cardiovascular risk factors associated with development of cardiovascular events in dialysis populations. The aim of the cross-sectional, retrospective study was the evaluation of the antihypertensive treatment schedule and control of blood pressure in relation to the guidelines in the group of hemodialysis patients. Additionally, we assessed the level of decrease in blood pressure by each group of hypotensive agents. Materials and Methods: 222 patients hemodialyzed in a single Dialysis Unit in three distinct periods of time-2006, 2011, and 2016-with a diagnosis of hypertension were enrolled in the study. The analysis of the antihypertensive treatment was based on the medical files and it consisted of a comparison of the mean blood pressure results reported during the six consecutive hemodialysis sessions. Results: The mean values of blood pressure before hemodialysis were as follows: 134/77, 130/74, and 140/76 mmHg, after hemodialysis 124/74, 126/73, and 139/77 mmHg in 2006, 2011, and 2016 respectively. The goal of predialysis blood pressure control (<140/90) was achieved by up to 64.3% of participants in 2006 as compared to 49.4% in 2016. Additionally, the postdialysis goal (<130/90) reached 57.1% of the study population in 2006 as compared to 27.1% of patients in 2016. The differences in percentage of patients using single, double, triple, and multidrug therapy during observation were not statistically significant. The most often used drugs were ß-blockers, diuretics, and calcium channel blockers in all points of the study. Blockades of the renin-angiotensin-aldosterone system in 2006 and calcium channel blockers in 2011 and 2016 were the drugs with highest impact on lowering blood pressure. Conclusions: The goal of predialysis or postdialysis blood pressure control was achieved in a lower percentage of patients during the period of the study. Blockade of renin-angiotensin-aldosterone system and calcium channel blockers decrease the blood pressure significantly. It is necessary to achieve better control of blood pressure in prevention of cardiovascular incidents.

Acute renal failure by rapidly progressive glomerulonephritis with IgA deposition in a patient concomitantly diagnosed with multibacillary Hansen's disease: a case report.

Rapidly progressive glomerulonephritis (RPGN) is a renal disease with an extensive differential diagnosis. This paper reports the case of a 55-year-old female patient diagnosed with Hansen's disease with acute progressive renal impairment after developing lower limb pyoderma. The association between Hansen's and kidney disease has been well documented, with glomerulonephritis (GN) ranked as the most common form of renal involvement. Post-infectious glomerulonephritis (PIGN) in adults has been associated with a number of pathogens occurring in diverse sites. The patient described in this case report had RPGN and biopsy findings suggestive of PIGN with C3 and IgA detected on immunofluorescence and kidney injury secondary to recent infection by Staphylococcus, a well-documented manifestation of renal impairment in patients with Hansen's disease.

[Amyloidosis and end-stage renal disease associated with leprosy]. / Amiloidose e insuficiência renal crônica terminal associada à hanseníase.

Renal involvement in leprosy includes glomerulonephritis, amyloidosis and tubulointerstitial nephritis. A 58-year-old man was admitted with complaints of lower limb edema and dyspnea. At admission, nitrogen retention, anemia, hyperkalemia and metabolic acidosis were observed, requiring hemodialysis. The patient had a history of lepromatous leprosy. A renal biopsy was performed that was compatible with amyloidosis. The patient had a stable outcome, but without renal function recovery and remained on regular hemodialysis. Leprosy should be investigated in every patient with renal function loss, particularly in those with cutaneous lesions or other manifestations suggestive of leprosy.

Amiloidose e insuficiência renal crônica terminal associada à hanseníase / Amyloidosis and end-stage renal disease associated with leprosy

O envolvimento renal na hanseníase é diverso, incluindo glomerulonefrites, amiloidose e nefrite túbulo-intersticial. Um homem de 58 anos foi admitido com edema de membros inferiores e dispnéia. Na admissão, havia retenção de escórias nitrogenadas, anemia, hipercalemia e acidose metabólica, com necessidade de hemodiálise. Referia história de hanseníase virchoviana. Foi realizada biopsia renal, compatível com amiloidose. O paciente evoluiu estável, sem recuperação da função renal, permanecendo em tratamento hemodialítico. A hanseníase deve ser investigada em todo paciente com perda de função renal, sobretudo naqueles que apresentam lesões cutâneas ou outras manifestações sugestivas de hanseníase.

Renal involvement in leprosy includes glomerulonephritis, amyloidosis and tubulointerstitial nephritis. A 58-year-old man was admitted with complaints of lower limb edema and dyspnea. At admission, nitrogen retention, anemia, hyperkalemia and metabolic acidosis were observed, requiring hemodialysis. The patient had a history of lepromatous leprosy. A renal biopsy was performed that was compatible with amyloidosis. The patient had a stable outcome, but without renal function recovery and remained on regular hemodialysis. Leprosy should be investigated in every patient with renal function loss, particularly in those with cutaneous lesions or other manifestations suggestive of leprosy.

Effectiveness of hemodialysis in acute dapsone overdose-a case report.

The use of dapsone is increasing even though overdose is rarely reported and physicians must be aware of its toxicity and management. Mortality can occur due to methemoglobinemia and hemolytic anemia. Although activated charcoal and methylene blue are recommended, the use of hemodialysis is reported only in few studies. Literature on the kinetic profile indicates that 50% to 80% of dapsone is protein bound and indicates a possibility to dialyze the unbound form. This study describes a case of deliberate severe dapsone overdose with cyanosis, methemoglobinemia, and hemolytic anemia, which improved after repetitive hemodialysis.

Effect of oral granisetron in uremic pruritus.

BACKGROUND: Renal itch is a relatively common and distressing problem for patients with chronic renal failure. Granisetron, is a potent and selective inhibitor of 5-HT3 receptors. There have been some studies about the effect of ondansetron in uremic pruritus and one case report has recently described relief of renal itch with granisetron. AIMS: To evaluate the effect of Granisetron on uremic pruritus in Continuous Ambulatory Peritoneal Dialysis (CAPD) and Hemodialysis (HD) patients. METHODS: To study the prevalence of uremic pruritus, patients on CAPD and HD were asked to complete a pruritus questionnaire. Their replies were scored based on numerical scales. Pruritus was graded, according to the total points for each patient, as mild, moderate or severe. Fourteen patients with moderate to severe pruritus were enrolled in the trial. During treatment, patients received granisetron (1 mg tablet twice a day P.O), for a period of 1 month. They were asked to score the severity of pruritus twice a day. RESULTS: Seventy seven percent of the patients responded to the treatment and at 1 st, 2 nd and 4 th week the mean values of the pruritus scores were 23, 16 and 8 points respectively. Before starting treatment the score was 31 points (P =0.03). Weekly clinical and laboratory examination showed no important side effects. CONCLUSION: Granisetron might be an effective, safe and well tolerated drug for the treatment of uremic pruritus.

[Transferrin microheterogeneity in patients treated by maintenance haemodialysis]. / Mikroheterogennosc transferyny u chorych leczonych powtarzana hemodializa.

Transferrin (Tf) plays a crucial role in iron transport in the human body. In physiologically status Tf occurs in four variants. The concentration of Tf and its variants is changing in several conditions, especially during acute phase response, which may take place in end-stage renal disease (ESRD). The aim of this study was the assessment of the associations between changes of glycosylation of transferrin and selected blood cell count and iron metabolism parameters in ESRD patients treated by maintenance hemodialysis (mHD) with long lasting anaemia despite treatment by rHuEPO. Studies were carried out on a group of 55 ESRD patients treated by HD (ESRD group). The reference values were obtained from a group of 20 healthy volunteers (HV group). The Tf concentration was determined by the rocket immunoelectrophoresis according to Laurell. To estimate the microheterogenity of Tf the crossed affinoimmunoelectrophoresis according to Bog-Hansen was used. The concentration of selected hematological variables, and selected liver metabolism variables was assessed by routine laboratory tests, while the concentration of cytokines was measured by ELISA method, and selected acute phase proteins, i.e. C-reactive protein, by immunonephelometry method. Tf in studied sera was divided into four variants Tf1, Tf2, Tf3, Tf4. The percentage contents of variants in HV was Tf1=4%, Tf2=9%, Tf3=82%, Tf4=4%. In the sera of ESRD group the percentage contents of the Tf1, Tf2, Tf4 variants increased to 9%, 16%, 10% respectively, while the Tf3 variant decreased to 65%. Serum concentration of Tf was lower (1441 +/- 526 mg/L) in ESRD patients (p<0.0001) vs. 3539 +/- 955 mg/L in HV group. During this study we have revealed that the quantity and the quality of Tf is changing in ESRD patients. The observed correlations between concentration of Tf3 and selected hematological variables and also between Tf3 and rHuEPO, suggests that the decrease concentration of the Tf3 may lead to an impaired iron transport to the cells and may be one of the factors affecting anaemia in patients treated by HD and rHuEPO.

Cutaneous manifestations in patients with chronic renal failure on hemodialysis.

BACKGROUND: Chronic renal failure (CRF) presents with an array of cutaneous manifestations. Newer changes are being described since the advent of hemodialysis, which prolongs the life expectancy, giving time for these changes to manifest. AIM: The aim of this study was to evaluate the prevalence of dermatologic problems among patients with chronic renal failure (CRF) undergoing hemodialysis. METHODS: One hundred patients with CRF on hemodialysis were examined for cutaneous changes. RESULTS: Eighty-two per cent patients complained of some skin problem. However, on examination, all patients had at least one skin lesion attributable to CRF. The most prevalent finding was xerosis (79%), followed by pallor (60%), pruritus (53%) and cutaneous pigmentation (43%). Other cutaneous manifestations included Kyrle's disease (21%); fungal (30%), bacterial (13%) and viral (12%) infections; uremic frost (3%); purpura (9%); gynecomastia (1%); and dermatitis (2%). The nail changes included half and half nail (21%), koilonychia (18%), onychomycosis (19%), subungual hyperkeratosis (12%), onycholysis (10%), splinter hemorrhages (5%), Mees' lines (7%), Muehrcke's lines (5%) and Beau's lines (2%). Hair changes included sparse body hair (30%), sparse scalp hair (11%) and brittle and lusterless hair (16%). Oral changes included macroglossia with teeth markings (35%), xerostomia (31%), ulcerative stomatitis (29%), angular cheilitis (12%) and uremic breath (8%). Some rare manifestations of CRF like uremic frost, gynecomastia and pseudo-Kaposi's sarcoma were also observed. CONCLUSIONS: CRF is associated with a complex array of cutaneous manifestations caused either by the disease or by treatment. The commonest are xerosis and pruritus and the early recognition of cutaneous signs can relieve suffering and decrease morbidity.

Lithium poisoning: pharmacokinetics and clearance during different therapeutic measures.

The clinical features and pharmacokinetics of 22 lithium overdoses are described. Effectiveness of different treatment regimens regarding elimination of lithium is discussed. Origin of overdose was due to deliberate poisoning or precipitated by concomitant diseases, coadministration of drugs, or combination of both. Treatment included supportive care, diuretics (15/22), hemodialysis (HD; 9/22), and mechanical ventilation (3/22). Severity of lithium intoxication was classified in 50% as I degrees, in 41% as II degrees, and in 9% as III degrees according to Hansen and Amdisen. Renal impairment on admission was diagnosed in 82% of the patients. Half-life of lithium in serum was 3.5 +/- 0.8 hours during the first HD, and 29 +/- 14 and 29 +/- 6 hours during therapy with diuretics or supportive treatment, respectively. Lithium clearance during HD was 160 +/- 15 mL/min, and renal clearance during HD or treatment with diuretics was approximately 20 and 15 +/- 9 mL/min, respectively. Renal lithium clearance was not influenced by HD therapy. There was no difference regarding half-life and clearance between the group that had an unspecific treatment or the group treated with diuretics. Hemodialysis is the therapy of choice for emergent extracorporeal lithium elimination. Renal impairment and interaction with other drugs were the main reasons for intoxication; thus, more cautious prescription or more frequent supervision of this patient group is warranted. It seems that treatment with diuretics does not have a beneficial effect in the overdose setting.

End-stage renal disease in leprosy.

BACKGROUND: Leprosy or Hansen's disease (HAD) undoubtedly remains an emergency in certain countries. It is an ancient deforming disease caused by Mycobacterium leprae. The countries with the highest endemic leprosy rate in 2000 were Brazil, India and Madagascar. In Italy, the old epidemic has been defeated and there are approximately 400 patients under constant monitoring with three to four new cases per year involving Italian residents. The kidney is one of the target organs during the splanchnic localization of leprosy. The histopathological renal lesion spectrum includes glomerulonephritis (GN), renal amyloidosis (RA) and interstitial nephritis (IN). Both proteinuria and chronic renal failure are the main clinical expressions of renal damage in leprosy. To the best of our knowledge, very little is reported concerning end-stage renal disease (ESRD) in leprosy patients both in the most important national and international renal registries and in the available literature. This study aimed to report the long-term experience of our department in this field. METHODS: To achieve this, we analyzed retrospectively the HAD Center (Gioia del Colle) database at ourhospital. RESULTS: Eight leprosy patients were dialyzed from 1980 to June 2003 (six males and two females), with a mean age of 61.0+/-8.9 SD yrs (range: 51-76) and a mean HAD duration of 36.1+/-5.1 yrs. The first clinical nephropathymanifestations were non-nephrotic proteinuria associated with chronic renal failure in four patients, and nephrotic proteinuria in four patients. Kidney biopsies performed in three patients showed two had RA, and one had IN. Two patients were treated initially by peritoneal dialysis; they were then switched to hemodialysis (HD) after 3 and 10 months because of recurrent peritonitis. HD treatment lasted 40.6+/-31.4 months (range: 9-101). Six patients died, one due to hyperkalemia, one because of a technical dialysis accident, and the remainder due to causes unrelated to the dialysis treatment. Two patients are still alive, treated with HD for 17 and 44 months. CONCLUSIONS: Uremia represents a late complication of leprosy and has a multifactorial genesis, although RA is among the most frequent causes, conventional bicarbonate HD appears to offer good results in the treatment of uremia in leprosy patients.

Effects of novel manufacturing technology on blood and dialysate flow distribution in a new low flux "alpha Polysulfone" hemodialyzer.

The main target for low flux hemodialyzers is an efficient low molecular weight solutes clearance. Such efficiency is largely dependent on the optimization of diffusion between blood and dialysis solution. The diffusion process can be impaired if there is a mismatch between blood and dialysate flow distribution in the dialyzer. Thus optimized flow distribution both in the blood and dialysate compartment becomes quintessential for the maximal efficiency of the diffusion process within the hemodialyzer. The present paper describes the distribution of the blood and dialysate flows in a new low flux polysulfone hollow fiber hemodialyzer characterized by a specific undulation of the fibers and a new cutting technology of the fibers for an improved micro-flow condition in the blood compartment headers. Twelve Diacap alpha Polysulfone LO PS 15 (1.5 sqm) (B. Braun Medizintechnologie, Melsungen Germany) were employed for the study. Six were analyzed in vitro and six were studied in vivo. Blood flow distribution was studied in vitro by dye injection in the blood compartment during experimental extracorporeal circulation utilizing human blood with hematocrit adjusted at 33%. Sequential images were obtained with a helical scanner in a fixed longitudinal section of the dialyzer 1 cm thick. Average and regional blood flow velocities were measured utilizing the reconstructed imaging sequence. The method allowed the calculation of single fiber blood flow (SF Qb) and the mass transfer zone (MTR) definition in digitally subtracted images. The patterns 20-10 and 40-30 were utilized. The same technology was used to evaluate flow distribution in the dialysate compartment after dye injection in the Hansen's connector. Regional dialysate flow was calculated in central and peripheral sample areas of 1 cm2. Six in vivo hemodialysis treatments on patients with end stage renal disease were performed at three different blood flow rates (250-350 and 450 ml/min) in order to measure urea, creatinine and phosphate clearance. Macroscopic and densitometrical analysis revealed that flow distribution was homogeneous in the blood compartment while in the dialysate compartment a slight difference between the peripheral and central regions in terms of flow velocity was observed. This however was not generating channeling phenomena. Urea creatinine and phosphate clearances were remarkably high and so were the Kt/V observed in all sessions, especially in relation to the studied blood flows. In conclusion, a significant blood to dialysate flow match with optimized countercurrent flow condition was observed in the studied hollow fiber hemodialyzers. Such optimization might be due both to the improved dialyzer design at the level of the blood header and to the specific fiber undulation that prevents dialysate channeling.

Comparison of patients hemodialyzed for lithium poisoning and those for whom dialysis was recommended by PCC but not done: what lesson can we learn?

AIMS: To compare patients for whom hemodialysis was done for lithium poisoning and those for whom it was recommended by the poison control centre (PCC) but not done and to evaluate the effect of withholding hemodialysis on outcomes. METHODS: All lithium overdoses brought to the attention of the PCC were prospectively followed from January 1 to December 31, 1996. Patients for whom hemodialysis was done were compared with those for whom it was recommended but not done in terms of clinical presentation, lithium elimination half-life, need for transfer to another centre for hemodialysis, and outcome (death, or sequel or recovery). RESULTS: A total of 205 cases of lithium overdoses were collected including 110 with levels higher than 1.5 mmol/l. There were 12 acute lithium overdoses; no patients required hemodialysis and there were no sequel or deaths. There were 174 acute on chronic overdoses; hemodialysis was recommended in 9 patients but only 6 underwent hemodialysis; one patient died during hemodialysis but no other had sequel. There were 19 chronic poisonings; hemodialysis was recommended in 9 patients but only 2 had hemodialysis, a third patient underwent hemodialysis despite it not being recommended; one patient died without hemodialysis and one other had sequel after hemodialysis. No difference were observed between the groups for age, sex, type of poisoning (acute on chronic/chronic), levels (initial/peak/6 hours/extrapolated at 30 hours), time of presentation post-ingestion, presence of co-ingestants, symptoms and signs, Hansen and Amdisen grade, initial creatinine, time of recommendation to perform hemodialysis (daytime or nighttime), need to transfer patients to another centre to perform hemodialysis, and outcome. Patients with acute on chronic poisoning that were not hemodialyzed had longer elimination half-life than those for whom hemodialysis was done even before hemodialysis was performed: 50.1 +/- 13.6 h (n = 3) versus 12.9 +/-12.1 (n = 3) (p = 0.007), respectively. CONCLUSION: No difference was observed between patients for whom hemodialysis was done and those for whom it was recommended by PCC but not done. Despite the death of one patient clearly associated with voluntary withholding hemodialysis, sequel was not seen in that group. The indications for hemodialysis in lithium poisoning should be reconsidered to include only the more severe cases.

Serious side effects of rifampin on the course of WHO/MDT: a case report.

A male born in 1935 was diagnosed as having lepromatous leprosy when he was 17 years old. In addition to dapsone (DDS) monotherapy, he had been treated with rifampin (RMP) for 2 terms: first with 450 mg a day for 2 years when he was 39 years old; second with 150 mg a day for 2 months after a 1-year interval from the first regimen. During these entire courses with RMP, no complication was noted. When he was 64 years old in 1999, a diagnosis of relapsed borderline tuberculoid (BT) leprosy was made, and he was started on the multibacillary (MB) regimen of the World Health Organization multidrug therapy (WHO/MDT). After the third dose of monthly RMP, he developed a flu-like syndrome and went into shock. A few hours later, intravascular hemolysis occurred followed by acute renal failure. He was placed on hemodialysis for 7 series and recovered almost completely about 2 months later. The immune complexes with anti-RMP antibody followed by complement binding may have accounted for these symptoms. Twenty-four reported cases of leprosy who had developed side effects of RMP under an intermittent regimen were analyzed; 9 of the cases had had prior treatment with RMP but 15 had not. Adverse effects were more likely to occur in MB cases and were more frequent during the first 6 doses of intermittent regimens. The cases with prior treatment with RMP had had a higher incidence of serious complications such as marked hypotension, hemolysis and acute renal failure. However, many exceptions were also found, and we could not verify any fully dependable factor(s) to predict the side effects of RMP. More field investigation is desirable, and monthly administration of RMP must be conducted under direct observation through the course of WHO/MDT.

Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial.

Our observation that thalidomide administration to a dialysis patient with leprosy alleviated his pruritus led us to conduct this short-term study to assess the efficacy of the drug in this regard. From 210 hemodialysis patients, 29 cases of refractory uremic pruritus were entered into the study. Patients were instructed to score their symptoms from 0 to 3, three times a day and assigned to receive thalidomide or placebo at bed time for 7 days. After a washout period of 7 days, drugs were crossed over. Response was defined as a reduction of at least 50% in the pruritus scoring. Eighteen patients finished the study. In the first phase, 55% of patients responded showing a mean reduction in their pruritus scoring of 78% (p < 0.05 vs. placebo); no response to placebo was observed. A similar proportion of patients responded to thalidomide in the second phase with a mean reduction in their pruritus scoring of 81%. In conclusion, thalidomide can be a precious tool in the handling of uremic pruritus unresponsive to available therapy.

The prevalence of human T-cell leukemia virus type I infection in patients with hematologic and nonhematologic diseases in an adult T-cell leukemia-endemic area of Japan.

In order to clarify the prevalence of human T-cell leukemia virus type I (HTLV-I) infection in the Kagoshima district, Japan, a highly endemic area for HTLV-I, antibodies for HTLV-I (anti-HTLV-I) were examined in the sera of 6167 from healthy residents and patients with various hematologic and nonhematologic diseases. In healthy residents, including blood donors, the prevalence of anti-HTLV-I was 11.9% (562/4741 persons). The prevalence increased with age, and was significantly higher in in females than in males (P less than 0.01). The prevalence of anti-HTLV-I in blood donors was 8.5%. In In hematologic diseases, the prevalence of anti-HTLV-I was 98.3% in ATL, 28.9% in lymphoproliferative disorders except ATL, and 10.6% in myeloproliferative disorders. In nonhematologic diseases, the prevalence of anti-HTLV-I was shown to be 29.5% in pulmonary tuberculosis, 25.8% in leprosy, 33.8% in chronic renal failure (CRF), 21.9% in autoimmune diseases, and 47.8% in strongyloidiasis. The various diseases except myeloproliferative disorders had significantly higher prevalence of anti-HTLV-I than healthy residents (P less than 0.01 or 0.05). For autoimmune diseases, the prevalence of anti-HTLV-I in patients with blood transfusion (55.6%) was higher than in those without blood transfusion (8.7%), and healthy residents. In hemodialysis patients with CRF who had received blood transfusions the prevalence of anti-HTLV-I increased with the number of blood transfusions. Therefore, HTLV-I transmission via blood transfusion would partially explain these high prevalence of anti-HTLV-I. However, the prevalence of anti-HTLV-I in hemodialysis patients with CRF was statistically higher than that in healthy residents, regardless of blood transfusion (P less than 0.01). Furthermore, hemodialysis patients showed significantly higher prevalence of anti-HTLV-I than healthy residents, even at a younger age. Patients with pulmonary tuberculosis and leprosy showed the same results as hemodialysis patients. These results suggest that possibility that HTLV-I infection has some relation not only to ATL but also to other diseases. Therefore, it seems very important to halt the spread of HTLV-I transmission as soon as possible.

Use of glutaraldehyde for disinfection in dialysis.

We compared Cidex HD Disinfecting Solution (CHD), a brand of glutaraldehyde disinfectant, alone and with bleach (B) to formaldehyde (F) with bleach for disinfection and cleaning of hemodialysis equipment. Two Drake-Willock central delivery systems (CDS) with 15 accompanying bedside stations and one Drake-Willock 4216 single patient delivery system (SPS) were used. The CDS designated #1, delivered dialysate to bedside stations 1 through 9, while CDS#2 supplied bedside stations 10 through 16. The study was conducted in three stages. Stage I used F six nights per week and B cleaning Wednesday (CDS#1/SPS) versus F Monday, Wednesday, and Friday with B on Wednesday (CDS#2) for four weeks. Stage II compared CHD six nights/week versus CHD Monday, Wednesday, and Friday for eight weeks. Stage III compared CDH six nights/week with B cleaning on Wednesday versus CHD on Monday, Wednesday, and Friday with B cleaning on Wednesday for four weeks. Samples of pretreated water were collected aseptically on Mondays, Wednesdays, and Fridays each week from the following sites: pre/CDS, inflow Hansen-bedside stations #5, #13, and SPS and pre-blood detector on BS #5, #13, and the SPS. During the study, 763 samples were cultured. Microbiological test results were reported as colony forming units per ml (CFU/ml). The CFU/ml were obtained by filtrating a 10 ml aliquot through a 0.45 mu filter, the filter transferred to a petri dish containing standard plate count agar and counted.(ABSTRACT TRUNCATED AT 250 WORDS)