Vol 86, No 6 (2014)

Editorial
Chronic kidney disease and vascular dementia
Mukhin N.A., Fomin V.V., Damulin I.V., Rogova I.V.
Abstract
The paper shows the value of chronic kidney disease as a population-wide determinant of vascular dementia, including moderate cognitive impairments. It discusses the role of risk factors of cardiovascular events, including those associated with chronic kidney disease, in the development of vascular dementia and moderate cognitive impairments.
Terapevticheskii arkhiv. 2014;86(6):7-10
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Quality of life and cognitive functions in patients with end-stage renal failure on hemodialysis using a succinate-containing dialyzing solution
Smirnov A.V., Vasil'eva I.A., Nesterova O.B., Golubev R.V., Vasil'ev A.N., Korosteleva N.I., Starosel'skiĭ K.G.
Abstract
AIM: To assess changes in quality of life (QL) and cognitive functions in patients with end-stage renal failure (ESRF) treated with hemodialysis using a succinate-containing dialyzing solution (SCDS)/MATERIAL AND METHODS: Sixty-seven patients with ESRF on hemodialysis using SCDS were examined. The investigators determined QL indicators using a Russianized variant of the Kidney Disease Quality of Life Short Form (KDQOL-SF) and the indicators of cognitive functions by the Benton visual retention test intended to evaluate visual short-term memory. The 6-minute walk test was used to evaluate exercise tolerance. The patients were examined before and 6 months after initiation of SCDS use/RESULTS: Following 6 months of SCDS treatment, the patients showed positive changes in a number of QL indicators. Their exercise capacity (p=0.03) and the quality of sleep (p=0.03), and social interaction (p=0.02) were improved. The magnitude of the complaints related to disease and treatment decreased (p=0.001). The level of patient frustration was reduced (p<0.001). Different limitations associated with chronic kidney disease and dialysis therapy came to disturb the patients to a lesser degree (p=0.02). The Bentoin visual retention test exhibited fewer errors (p=0.04)/CONCLUSION: Hemodialysis treatment with SCDS improved a number of QL indicators and cognitive functions in the patients.
Terapevticheskii arkhiv. 2014;86(6):11-17
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Investigation of 70-kDa heat shock protein in the serum and urine of patients with chronic glomerulonephritis
Chebotareva N.V., Neprintseva N.V., Bobkova I.N., Kozlovskaia L.V.
Abstract
AIM: To determine the levels of 70-kDa heat shock protein (HSP70) in urine and anti-HPS70 antibodies (Abs) in serum and to assess their clinical and prognostic value in patients with different forms of chronic glomerulonephritis (CGN)/MATERIAL AND METHODS: Seventy-nine patients with CGN, including 15 with inactive nephritis (Group 1), 35 with active CGN and preserved renal function (Group 2), 14 with the highest CGN activity and transient creatininemia (Group 3), and 15 with persistent proteinuria and chronic renal failure (Group 4) were examined. ELISA was used to estimate urinary HSP70 levels and serum anti-HSP70 Abs in the examined groups/RESULTS: The patients with active CGN were found to have higher excretions of urinary HSP70 and serum anti-HSP70 Abs. Urinary HSP70 excretion was significantly higher in the patients with transient renal function (Group 3) than in those from the other groups. At the same time, there was a decrease in serum anti-HSP70 Abs, which was a poor factor of persistent nephrotic syndrome despite immunosuppressive therapy (IST). Despite long-term IST, the nephrotic syndrome was persistent in 9 (60%) of the 15 patients with low serum Ab titers. At the same time, 8 (80%) of the 10 patients with higher serum Ab titers responded to IST during 9 months/CONCLUSION: The investigation demonstrates the great value of HSP70 as an index of the severity of lesion and the activation of kidney self-defense mechanisms in patients with CGN. Determination of serum anti-HSP70 Abs may be used to assess the prognosis of CGN.
Terapevticheskii arkhiv. 2014;86(6):18-23
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Clinical significance of serum and urinary biomarkers for water-salt metabolism in patients with proteinuric forms of chronic glomerulonephritis
Pulin A.A., Brovko M.I., Kustova T.I., Kozlovskaia L.V., Fomin V.V., Mukhin N.A.
Abstract
AIM: To determine the nature and magnitude of changes in the detectable serum and urinary biomarkers of water-salt metabolism in patients with proteinuric forms of chronic glomerulonephritis (CGN), their importance for assessing the activity and prognosis of the disease/MATERIAL AND METHODS: Forty-seven patients with CGN were examined. Group 1 included 10 patients with nephrotic syndrome (NS) and decreased renal function; Group 2 comprised 16 patients with persistent NS and normal renal function; Group 3 consisted of 10 patients with partial remission of NS; Group 4 included 11 patients with active hematuric CGN. A control group consisted of 9 healthy individuals matched for gender and age with the patients with CGN. The serum level of copeptin and the urinary excretion of aquaporine-2 (AQP-2) and kidney injury molecule-1 (KIM-1) were determined by indirect enzyme-linked immunosorbent assay (ELISA)/RESULTS: In the NS patients with and without renal dysfunction, the serum copeptin concentration was significantly higher than that in those with partial remission of NS or hematuric CGN and in the controls. In the patients with hematuric CGN, this indicator was virtually different from that in the control group. Urinary AQP-2 excretion was significantly similar in 3 NS groups. In the patients with hematuric CGN, the urinary AQP-2 concentration was higher than that in those with NS, but it was significantly lower than in the control group. The highest urinary excretion of KIM-1 was found in the patients with NS and diminished renal function while its excretion was significantly lower in the patients with NS and stable renal function, as in those with partial remission of NS. The lowest values were seen in the patients with hematuric CGN and in the control group; the differences between these groups were statistically insignificant. Correlation analysis showed that there was an inverse correlation between serum copeptin and urinary AQP-2 levels and between urinary AQP- 2 and KIM-1 levels/CONCLUSION: Serum copeptin levels and urinary AQP-2 secretion may be used to assess the activity of CGN and NS and to evaluate therapeutic effectiveness. The determination of urinary KIM-1 excretion may be of the same practical value in patients with NS. It has been shown that the concentrations of copeptin, APQ-2, and KIM-1 may be used as a differential diagnostic criterion for hematuric CGN.
Terapevticheskii arkhiv. 2014;86(6):24-29
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Alterations of the complement system in patients with catastrophic antiphospholipid syndrome
Dem'ianova K.A., Kozlovskaia N.L., Shilov E.M., Bobrova L.A., Kozlov L.V., Sorokin I.D., Roshchupkina S.V., Nikiforova N.V., Dobrosmyslov I.A., Romanova M.D., Kireeva V.A., Kuchieva A.M.
Abstract
AIM: To investigate alterations of the complement system in patients with catastrophic antiphospholipid syndrome (CAPS)/MATERIAL AND METHODS: Four patients (2 men aged 23 and 40 years and 2 women aged 39 and 58 years) diagnosed as having CAPS, including 3 patients with systemic lupus erythematosus and secondary antiphospholipid syndrome (APS) and 1 patient with primary APS, were examined. The activity of the complement components C1-C5 and total hemolytic activity were determined in all the patients at the moment of an acute episode and in 1 patient after treatment/RESULTS: The activity of the studied complement components and total hemolytic complement activity proved to be significantly decreased in all the patients. That of complement components recovered after treatment using fresh frozen plasma. The possibility and mechanisms of complement system activation in the patients with CAPS are discussed/CONCLUSION: The preliminary results obtained by the examination of few cases may lead to the conclusion that the complement system may be involved in the development of CAPS.
Terapevticheskii arkhiv. 2014;86(6):30-37
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Effect of loop diuretics with different elimination half-lives on natriuresis changes and indicators characterizing the state of renal tubulointerstitial tissue
Arutiunov G.P., Dragunov D.O., Sokolova A.V.
Abstract
AIM: To investigate the effect of loop diuretics with different elimination half-lives on natriuresis (NU) changes in patients with hypertensive disease (HD) and chronic heart failure (CHF)/MATERIAL AND METHODS: Fifty-six patients who had signs of progressive CHF and needed diuretic therapy were selected from a group of the patients who had participated in our previous study of the types of natriuretic curves. They all received torasemide SR or torasemide IR/RESULTS: It has been shown that the type of a natriuretic curve may be variable in the patients. In the toracemide IR group, NU worsens more frequently and earlier than in the toracemide SR group (p < 0.05). The type of the curve is associated with elevated Tamm-Horsfall protein (THP) levels, its transition from one to another type, and the duration of HD to the greatest degree. It has been found that the longer history of HD is, the higher effect of angiotensin II is. The probability of transition of the natriuretic curve from type 3 to 2 is 83.93% (odds ratio 11.667) from type 2 to 1 is 92.86% (odds ratio 120.00)/CONCLUSION: With time and altered NU, there is a significant deterioration of sodium excretion, and an increase in THP excretion, which is a marker for progressive tubulointerstitial fibrosis, and angiotensin II activity increases, which gives proof to the necessity of monitoring NU.
Terapevticheskii arkhiv. 2014;86(6):38-44
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Clinical value of the determination of markers for endothelial dysfunction (endothelin-1, microalbuminuria) and tubulointerstitial tissue lesion (Β2-microglobulin, monocyte chemotactic protein-1) in hypertensive patients with uric acid metabolic disorders
Stakhova T.I., Shcherbak A.V., Kozlovskaia L.V., Taranova M.V., Balkarov I.M.
Abstract
AIM: To identify the risk factors of kidney injuries in hypertensive patients with uric acid (UA) metabolic disorders in order to choose the optimal management tactics, by analyzing the changes in markers for endothelial dysfunction (endothelin-1 (ET-1), microalbuminuria (MAU), intima-media thickness (IMT)) and tubulointerstitial tissue lesion (Β2-microglobulin (Β2-MG, monocyte chemotactic protein-1 (MCP-1))/MATERIAL AND METHODS: Eighty-one patients with grade 1 hypertension without associated diseases, diabetes mellitus, or metabolic syndrome were examined. There were 3 study groups: 1) hyperuricosuria (n=7); 2) hyperuricemia (n=53); 3) hyperuricemia and renal failure (n=6); and a control group of 15 hypertensive patients without UA metabolic disorders who were matched for age and gender with the patients of the study groups/RESULTS: The hypertensive patients with hyperuricemia, as compared with those without UA metabolic disorders, showed higher plasma concentrations of ET-1 (p=0.003) and MAU (p=0.009) and more marked increases in common carotid IMT (p=0.044), urinary excretion of Β2-MG (p=0.010), and MCP-1 (p=0.030). There were direct correlations between all the examined biomarkers and the degree of uricemia (Rs=0.453; р<0.001; Rs=0.411; р<0.001; Rs=0.322; р=0.067; Rs=0.537; р<0.001; and Rs=0.318; р=0.004, respectively) and between the markers of endothelial dysfunction and those of tubulointerstitial tissue lesion (Rs=0.295 for ET-1 and MCP-1; р=0.008; Rs=0.399 for ET-1 and Β2-MG; р<0.001; Rs=0.462 for MAU and Β2-MG; р<0.001; and Rs=0.188 for MAU and MCP-1; р=0.094). Multivariate analysis of the clinical and laboratory parameters under study confirmed the role of serum MCP-1, Β2-MG, MAU, creatinine levels as independent predictors for decreased relative urinary gravity, the clinical sign of tubulointerstitial tissue lesion/fibrosis, and that of a wider range of the indicators, such as MAU, ventricular septal thickness, glomerular filtration rate, relative urinary gravity, systolic blood pressure, MPC-1, low-density lipoproteins, as risk factors for renal filtrating dysfunction.
Terapevticheskii arkhiv. 2014;86(6):45-51
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Experience with active vitamin D metabolites in phosphorus-calcium metabolic disorders in patients with predialysis chronic kidney disease
Milovanova L.I., Dobrosmyslov I.A., Milovanov I.S.
Abstract
AIM: To evaluate the efficacy and safety of alfacalcidol and paracalcitol used to correct impaired phosphorus-calcium metabolism (PCM) in patients with predialysis chronic kidney disease (CKD)/MATERIAL AND METHODS: Examinations were made in 128 patients with Stages III-V CKD, including 89 (69.5%) patients with chronic glomerulonephritis, 30 (23.4%) with chronic tubulointerstitial nephritis, and 9 (7.1%) with hypertensive nephrosclerosis. Impaired PCM was detected in 90 (70.3%) of the examined patients. According to the pattern of the previous therapy, all the 90 CKD patients with PCM disorders were divided into 3 groups: 1) 32 patients with Stages IIIB-V CKD who had taken oral alfacalcidol 0.25 µg/day; 2) 28 patients with Stages IIIB-V CKD who had used oral paricalcitol 1 µg/day; 3) 30 patients with Stages IIIB-V CKD who had not received, as self- motivated, active vitamin D metabolites at the predialysis stage/RESULTS: Alfacalcidol and paricalcitol were quite satisfactorily tolerated by the patients. After 3 months of initiation of the use of these agents, Groups 1 and 2 patients with predialysis CKD and baseline elevated blood intact parathyroid hormone (iPTH) levels could not only achieve, but also maintain target blood iPTH levels. In the patients taking paricalcitol, the urinary protein level decreased more promptly; moreover, by the end of month 6 the reduction in blood pressure (BP) was more significant than in those using alfacalcidol (p<0.05). Comparison of the effects of angiotensin-converting enzyme inhibitors in combination with alfacalcidol or paricalcitol on BP changes and left ventricular mass index indicated that the most pronounced positive changes occurred when angiotensin-converting enzyme inhibitors were used in combination with paricalcitol/CONCLUSION: The use of paricalcitol in predialysis CKD with PTH hyperproduction results in not only normalization of the levels of both PTH and osseous isoenzyme of alkaline phosphatase, but also in significantly reduced daily proteinuria and regression of left ventricular hypertrophy and chronic heart failure.
Terapevticheskii arkhiv. 2014;86(6):52-56
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Prognostic value of allelic variants affecting the hemostatic system in the development of antiphospholipid syndrome and kidney lesion in patients with systemic lupus erythematosus
Borisov E.N., Krasnova T.N., Samokhodskaia L.M., Ivanitskiĭ L.V., Nikiforova N.V., Mukhin N.A.
Abstract
AIM: To analyze the prognostic value of the polymorphisms of the thrombophilic genes: plasminogen activator inhibitor type 1 (PAI-1) (–675 4G/5G), factor XIII (FXIII) (G485T), fibrinogen (FBG) (G(–455)A), glycoprotein Ia (GPIa) (C807T), glycoprotein IIIa (GPIIIa) (T106C), and p22phox (C242T), as well as protein genes involved in the pathogenesis of endothelial dysfunction: subunits of p22phox NADH-oxidase (p22phox) (C242T), endothelial NO-synthase (eNOS) (G894T), and methylenetetrahydrofolate reductase (MTHFR) (С677Т) for the development of antiphospholipid syndrome (APS) and a type of progressive lupous nephritis (LN) in patients with systemic lupus erythematosus (SLE)/MATERIAL AND METHODS: One hundred patients with SLE were examined and, according to the presence of clinical and laboratory signs of APS were divided into 2 groups: 1) 50 SLE patients with APS; 2) 50 SLE patients without APS who were matched for gender and age with Group 1 patients. The gene polymorphisms were analyzed using standard molecular genetic techniques. The frequency of clinical manifestations of APS and the type of progressive nephritis were analyzed in view of the genotypes of the patients/RESULTS: Comparison of SLE patients with and without SLE revealed no statistically significant differences in the rates of alleles and genotypes. The patients with arterial and/or venous thrombosis in the presence of APS more frequently displayed a minor allele (T) and genotype (TT) of the p22phox gene than those with APS without thrombosis: T, 64.5 and 34%, respectively (p=0.033); TT, 36 and 7% (p=0.021); odds ratio (OR), 2.1 at 95% confidence interval (CI), 1.5 to 22.7). In the APS patients with livedo reticularis, the minor allele (T) and genotype (TT) of the eNOS gene were more common than in those without livedo: T, 33 and 10%, respectively (p=0.019); TT, 15 and 0% (p=0.031); OR, 2.49 at 95% CI, 1.2 to 28.9). In the patients with AFS and rapidly progressive LN (RPLN), the minor allele (T) and genotype (TT) of the MTHFR gene were much more frequently encountered: T, 46 and 27%, respectively (p=0.038); TT, 30 and 0% (p=0.033); OR, 3.1 at 95% CI, 1.4 to 32.7). The group of patients without APS exhibited no relationship between the examined polymorphisms and kidney lesion/CONCLUSION: The mutant allele of the p22phox gene increases the risk of arterial and venous thrombosis; the polymorphism of the eNOS gene may be related to the higher incidence of impaired blood microcirculation in SLE concurrent with APS. The risk of RPLN in SLE patients with APS is probably associated with MTHFR gene mutation.
Terapevticheskii arkhiv. 2014;86(6):57-62
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Osteoprotegerin and fibroblast growth factor 23 in the development of cardiovascular events in chronic kidney disease
Dzgoeva F.U., Gatagonova T.M., Bestaeva T.L., Sopoev M.I., Bazaeva B.G., Khamitsaeva O.V.
Abstract
AIM: To study the role of the bone mineral metabolic mediators osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF-23) in the mechanisms of cardiovascular events (CVEs) in chronic kidney disease (CKD)/MATERIAL AND METHODS: Sixty-eight patients (30 men and 38 women) aged 38 to 64 years (mean age 49±6.3 years) with Stages III-VD CKD were examined. The stages of CKD were determined in accordance with the NKF-K/DOQI guidelines; glomerular filtration rate was calculated using the CKD-EPI formula. Serum OPG and FGF-23 were examined in all the patients, by applying commercial enzyme immunoassay kits. Doppler echocardiography was performed to evaluate the morphofunctional state of the left ventricle (LV)/RESULTS: As renal failure progressed from Stage III to Stage VD CKD, the examined patients had higher serum OPG and FGF-23 concentrations. The levels of OPG and FGF-23 and the morphofunctional indicators of LV lesion, blood pressure, and anemia showed a strong direct correlation that preserved its significance in analyzing the factors in question in relation to the function of the kidneys and the pattern of cardiovascular system lesion/CONCLUSION: The morphogenetic proteins OPG and FGF-23 seem to play a significant role not only in bone remodeling processes, but also in the development of CVEs in CKD.
Terapevticheskii arkhiv. 2014;86(6):63-69
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Effect of tacrolimus on the results of living related kidney donor transplantation
Goriaĭnov V.A., Kaabak M.M., Babenko N.N., Morozova M.M., Agureeva L.I., Panin V.V., Platova E.N., Vinnitskiĭ L.I., Vorob'eva N.T.
Abstract
AIM: To elucidate whether and how tacrolimus affects the cumulative survival of patients after living related kidney donor transplantation/MATERIAL AND METHODS: The clinical materials of 246 related kidney transplant recipients, including 108 patients in whom tacrolimus (Prograf and Advagraf) Astellas Pharma US, Inc) was included in the immunodepression protocol (Group 1) and 138 patients who did not receive the agent (Group 2), were analyzed. Comparative analysis used the following tests: the Kaplan Meier test estimating the cumulative survival of recipients and transplants; the Cox test assessing the cumulative risk; and the log-rank test. Allorenal graft losses and mortality rates were also calculated./RESULTS: Mathematical analysis of the above indicators demonstrated that the allograft and survival rates were far higher (p<0.05) and the cumulative risk was much less in Group 1 (p<0.02). Graft losses and the recipients’ deaths were higher in Group 2/CONCLUSION: The analysis suggests that the incorporation of tacrolimus into the immunodepression therapy protocol positively impacts the results of lung related kidney donor transplantation.
Terapevticheskii arkhiv. 2014;86(6):70-73
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Electrocardiographic diagnosis of rural emergencies, by applying a tele-ECG recording and analysis system
Riabykina G.V., Vishniakova N.A.
Abstract
AIM: To identify emergencies in rural dwellers during electrocardiographic examination using a tele-electrogram (ECG) analysis (Easy ECG) system. Materials and methods. The easy ECG system connected 4 therapeutic-and-prophylactic institutions of a rural area and the town of Uryupinsk with the Research Institute of Cardiology, Russian Cardiology Research-and-Production Complex (Moscow). A total of 1,027 ECGs were recorded and analyzed in March 25, 2013 to November 11, 2013./RESULTS: Based on complaints, data of physical examinations, and results of ECG analysis, the investigators detected 188 (18.3%) emergency cases; 39 (3.8%) rural dwellers were first diagnosed as having emergencies. There were new found cases of acute coronary syndrome (n=2), focal cicatricial changes (n=11), including focal injury in the presence of left bundle-branch block (LBBB) (n=2), and ischemic cardiomyopathy (n=1) due to prior extensive myocardial infarction (as high as 28.2%). The frequent finding was intraventricular blocks (46.1%), including LBBB (n=4) and right bundle-branch block (n=1) (as high as 12.8%); the signs of left ventricular hypertrophy were encountered in 12 cases, as well as in 2 cases in the presence of LBBB (as high as 38.5%)/CONCLUSION: The findings show the value of bedside recording of ECG with its remote analysis in the absence of special diagnostic services. Each of the detected electrocardiographic syndromes is a risk factor of cardiac death.
Terapevticheskii arkhiv. 2014;86(6):74-83
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The specific features of kidney injury due to the abuse of saluretics and uncontrollable fasting in anorexia nervosa
Nikolaev A.I., Zakharova E.V., Tareeva A.B.
Abstract
The paper describes a case of severe preranal acute renal failure that was induced by the uncontrolled long-term use of furosemide and that was reversible after infusion therapy. Another case is a female patient with anorexia nervosa and end-stage uremia progressing to chronic tubulointerstitial nephritis. Some problems of the pathogenesis of kidney injury and its diagnostic difficulties in anorexia nervosa and diuretic abuse are discussed.
Terapevticheskii arkhiv. 2014;86(6):84-87
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Biomarkers of acute kidney injury: Current views and prospects
Kobalava Z.D., Villeval'de S.V., Efremovtseva M.A., Moiseev V.S.
Abstract
In the past decades, the incidence of acute kidney dysfunction has been steadily increasing, which is mainly due to rises in the prevalence of cardiovascular diseases and the survival of cardiac patients and to more common use of intervention examination and treatment methods. The early diagnosis of acute kidney injury (AKI) is made difficult by the delay in clinical symptoms and the elevated serum levels of creatinine as to cell damage, which chiefly appears as the expression of biomarkers. The new AKI biomarkers whose concentration changes significantly earlier than the serum creatinine levels increase have been recently identified. This has allowed Acute Dialysis Quality Initiative (ADQI) experts to develop consensus on the use of the biomarkers to diagnose AKI; a new concept of the diagnosis of AKI, by assessing not only the markers of renal function (serum creatinine and diuresis), but also those of injury, and the conceptual model of AKI are proposed.
Terapevticheskii arkhiv. 2014;86(6):88-93
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The current diagnosis and clinical prognostic value of kidney dysfunction in patients with coronary heart disease
Shafranskaia K.S., Bykova I.S.
Abstract
The problem of kidney dysfunction and its impact on outcomes in different groups of cardiac patients continue to being widely used. Kidney dysfunction is associated with a number of traditional cardiovascular risk factors. The use of new biomarkers, cystatin C in particular, to identify kidney injury can contribute to the improvement of early prediction of a risk for renal failure (RF). Cystatin C satisfies many characteristics as an ideal biomarker that can assist in not only detecting the early forms of kidney injury, but also in assessing the risk of RF, the needs for renal replacement therapy, and the risk of death in intensive care unit patients in cardiac clinics. Kidney involvement in many diseases, including those that are not initially regarded as renal, necessitates the elaboration of uniform approaches to managing patients with identified chronic RF, especially to the early prevention and treatment of its complications, such as anemia, phosphorus-calcium metabolic disorders, which substantially worsen the prognosis of other diseases.
Terapevticheskii arkhiv. 2014;86(6):94-99
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The main pathophysiological mechanisms of kidney injury in obstructive sleep apnea syndrome
Zelveian P.A., Dgerian L.G.
Abstract
Nowadays, obstructive sleep apnea syndrome (OSAS) has been established to promote both structural and functional changes in the kidneys. The basis for these changes is pathophysiological mechanisms, such as hyperproduction of free radicals and disruption of NO-mediated vasodilator responses, activation of the sympathetic autonomic nervous system and the renin-angiotensin-aldosterone system, endothelial dysfunction, development of renal venous hypertension, and stimulation of atrial natriuretic peptide production, which in turn results in increased intraglomerular pressure and glomerular hyperfiltration. In patients with OSAS, the kidneys may be damaged by OSAS-related abnormalities, such as hypertension, diabetes mellitus, metabolic syndrome, erythrocytosis, atherosclerosis, and cor pulmonale, which may also lead to kidney injury under isolated conditions and, when concurrent OSAS is present, may even aggravate the existing kidney injury.
Terapevticheskii arkhiv. 2014;86(6):100-105
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