Real world analysis of high-cut-off (HCO) hemodialysis with bortezomib-based backbone therapy in patients with multiple myeloma and acute kidney injury.

BACKGROUND: In patients with multiple myeloma (MM) free light chain-induced cast nephropathy is a serious complication associated with poor survival. High-cut-off (HCO) hemodialysis can reduce the amount of serum free light chains (sFLC), but data on its impact on clinical outcome is limited and contradictory. To gain further insights we collected real world data from two major myeloma and nephrology centers in Austria and the Czech Republic. METHODS: Sixty-one patients with MM and acute kidney injury, who were treated between 2011 and 2019 with HCO hemodialysis and bortezomib-based MM therapy, were analyzed. RESULTS: The median number of HCO hemodialysis sessions was 11 (range 1-42). Median glomerular filtration rate at diagnosis was 7 ± 4.2 ml/min/1.73m2. sFLC after the first HCO hemodialysis decreased by 66.5% and by 89.2% at day 18. At 3 and 6 months, 26 (42.6%) and 30 (49.2%) of patients became dialysis-independent. CONCLUSION: The widely used strategy combining HCO hemodialysis and bortezomib-based antimyeloma treatment is dissatisfactory for half of the patients undergoing it and clearly in need of improvement.

Thrombotic microangiopathy and pregnancy.

OBJECTIVE: The aim of this study is to draw attention to a nosological unit called thrombotic microangiopathy (TMA). This syndrome represents a serious pathological condition characterized by microangiopathic haemolytic anemia (MAHA), thrombocytopenia and various organ dysfunction. Patients are most often presented with symptoms of the HELLP syndrome but if the clinical picture is not restituted within 48-72 hours after delivery, other TMAs should be considered. SETTING: Department of Obstetrics and Gynecology, 1st Medical Faculty and General Teaching Hospital Prague; Clinic of Nephrology, 1st Medical Faculty and General Teaching Hospital Prague; Department of Obstetrics and Gynecology, Regional Hospital Kolín. DESIGN: Review article and case reports. METHODS: Review of the literature and description of two cases of TMA. CONCLUSION: The authors present a basic overview of the issue of TMA, which requires interdisciplinary cooperation of obstetricians, anesthesiologists, nephrologists and hematologists. In the second part of the article, we present two TMA case reports and finally show the differential diagnostic and therapeutic scheme as agreed by the authorities in the field.

Biomarkers in Immunoglobulin Light Chain Amyloidosis.

Immunoglobulin light chain amyloidosis (AL amyloidosis - ALA) is a monoclonal gammopathy characterized by presence of aberrant plasma cells producing amyloidogenic immunoglobulin light chains. This leads to formation of amyloid fibrils in various organs and tissues, mainly in heart and kidney, and causes their dysfunction. As amyloid depositing in target organs is irreversible, there is a big effort to identify biomarker that could help to distinguish ALA from other monoclonal gammopathies in the early stages of disease, when amyloid deposits are not fatal yet. High throughput technologies bring new opportunities to modern cancer research as they enable to study disease within its complexity. Sophisticated methods such as next generation sequencing, gene expression profiling and circulating microRNA profiling are new approaches to study aberrant plasma cells from patients with light chain amyloidosis and related diseases. While generally known mutation in multiple myeloma patients (KRAS, NRAS, MYC, TP53) were not found in ALA, number of mutated genes is comparable. Transcriptome of ALA patients proves to be more similar to monoclonal gammopathy of undetermined significance patients, moreover level of circulating microRNA, that are known to correlate with heart damage, is increased in ALA patients, where heart damage in ALA typical symptom.Key words: amyloidosis - plasma cell - genome - transcriptome - microRNA.

Increased levels of soluble ST2 in patients with active newly diagnosed ANCA-associated vasculitis.

OBJECTIVE: ST2, a member of the interleukin-1 receptor family, is selectively expressed on Th2 cells and mediates important Th2 functions. IL-33 is a specific ligand of ST2. The aim of the study was to determine whether serum levels of soluble ST2 (sST2) or IL-33 predict activity of the disease in patients with ANCA-associated vasculitides (AAV). METHODS: 139 AAV patients and 62 controls were studied. IL-33 and sST2 in the blood were measured with a commercially available ELISA. RESULTS: Newly diagnosed AAV patients had higher sST2 levels than controls (P < 0.01). Levels of sST2 were significantly higher in active newly diagnosed AAV patients than in patients with remission (P < 0.001). IL-33 levels were higher in AAV patients than in the control groups (P = 0.002). However, serum IL-33 levels were not increased in patients with active AAV compared to patients in remission. IL-33 levels were higher in patients with granulomatosis with polyangiitis than in patients with microscopic polyangiitis (P = 0.012). CONCLUSIONS: Serum sST2, but not serum IL-33, may be a marker of activity in AAV patients.

Rituximab use in patients with ANCA-associated vasculitis: clinical efficacy and impact on immunological parameters.

Rituximab (RTX) was reported effective in ANCA-associated vasculitis (AAV). We aimed to evaluate clinical efficacy of RTX in AAV along with its impact on immunological parameters. Eighteen RTX-treated AAV patients (M/F 11/7; median age 37.5; 15× PR3-ANCA, 3× MPO-ANCA; 16× relapsing/refractory, 2× first-line therapy) were enrolled. Clinical response, ANCA, total serum IgG levels and cellular immunity parameters were examined. The patients were followed up (FU) for a median of 26 months (range 3-82, 15 for ≥6 months). All patients achieved B cell depletion (lasting 3-24 months). No significant increase was noted in T cell or NK cell subpopulations. At 6 months, partial remission was achieved in 5/15 patients (33 %) and complete in 8 (53 %). The median prednisone dose (30..10 mg/d) and ANCA levels (17.2..2.7 IU/mL) decreased (p < 0.01). RTX retreatment was used in nine (8× pre-emptive, 1× relapse). Six patients relapsed (none of the pre-emptively treated). Three patients died of infection. IgG levels at 3 months decreased compared to baseline (9.0 vs 5.7 g/L, p < 0.01). Higher percentage of HLA-DR+CD3+ cells and lower percentage of CD4+CD45RA+ naive T cells persisted during FU. IFN-γ production increased at 6 months compared to baseline (27.3 vs 41.5 %). No significant change was noted in the intracellular IL-10 and IL-12 production. RTX helped to lower the glucocorticosteroids dose and withdraw cytotoxic drugs in most AAV patients. Hypogammaglobulinaemia was common but well tolerated. Peripheral circulating T cells remained activated despite B cell depletion.

Extended follow-up of the CYCLOFA-LUNE trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide or on cyclosporine A.

Objective To evaluate the extended follow-up of the CYCLOFA-LUNE trial, a randomized prospective trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide (CPH) or cyclosporine A (CyA). Patients and methods Data for kidney function and adverse events were collected by a cross-sectional survey for 38 of 40 patients initially randomized in the CYCLOFA-LUNE trial. Results The median follow-up time was 7.7 years (range 5.0-10.3). Rates of renal impairment and end-stage renal disease, adverse events (death, cardiovascular event, tumor, premature menopause) did not differ between the CPH and CyA group, nor did mean serum creatinine, 24 h proteinuria and SLICC damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. Conclusion An immunosuppressive regimen based on CyA achieved similar clinical results to that based on CPH in the very long term.

Can adequate treatment influence the postembolization syndrome and cytokine release in patients undergoing iatrogenic renal artery embolization?

The complete renal artery embolization is an alternative to surgical nephrectomy in seriously ill patients. Iatrogenic embolization can be used in many different conditions. Refractory nephrotic syndrome represents a very rare indication for embolization. Complete renal artery embolization has usually been complicated by postembolization syndrome (PES) which is characterized by flank pain and fever. Possible immunologic contribution to the PES leads some authors to the administration of corticosteroids to the patients undergoing embolization. We report here a cohort of 13 patients undergoing complete embolization of total 21 kidneys due to refractory nephrotic syndrome non-responding to the various specific treatment regimes. We treated our patients undergoing renal artery embolization according to special protocol containing combination of antibiotic drugs and corticosteroids (CS) to diminish PES and evaluated its influence to the cytokine production. The incidence of PES was less frequent and milder in comparison with the historical group of patients. Significant decrease in plasma levels of tumor necrosis factor α during first post-embolization day (8.37 pre- vs. 5.74 pg/ml post-embolization, P=0.0002) could partially explain the reduction of PES symptoms. The procedure was not complicated by severe complications and represents an elegant alternative to surgical procedure. The accurate timing of the embolization remains a controversial point in this intervention.

[Proteinuria in primary care]. / Proteinurie v ambulantní praxi.

Proteinuria is one of the main symptoms of renal impairment. It may manifest itself as a small amount of albumin in the urine (microalbuminuria) or as the nephrotic syndrome. Testing strips results should be considered as preliminary; a negative result does not exclude renal disease. At present, proteinuria is assessed as a total protein waste in the urine collected over 24 hours with up to 150 mg/day being considered a norm. Lately, the protein (albumin) to creatinine ratio in a sample of morning urine is being preferred (protein/creatinine ratio - PCR or albumin/creatinine ratio - ACR). More detailed nephrological examination should be performed if these reach pathological values (PCR > 15 mg/mmol a ACR > 3.5 mg/mmol). These assessments are not burdened by the same variability of values as with the 24-hour urine collection. A number of studies provided evidence on the role of proteinuria (as well as microalbuminuria) in accelerating a decline in glomerular filtration as well as its role as a risk factor of total and cardiovascular mortality. Therefore, this issue should receive appropriate attention and patients who are in a higher risk of renal impairment should be intentionally sought. These include diabetics, patients with heart disease, hypertension and patients with known personal or family history of renal disease. Only when a renal disease (and proteinuria is a clear symptom) is detected in time, targeted or symptomatic treatment can by initiated to slow down or even halt the disease progression to end stage renal disease. Despite this, more than 1/3 of patients entering chronic dialysis treatment have not been monitored. This significantly increases their morbidity and mortality, particularly within the first year of dialysis. General practitioners as well as internal medicine specialists, cardiologists and diabetologists play a fundamental role in screening of the high risk population.

The influence of vascular endothelial growth factor (VEGF) polymorphism on the progression of chronic glomerulonephritides.

Vascular endothelial growth factor is an important mediator in maintaining normal kidney functions. In addition, several lines of evidence show that up-regulation of this mediator in glomeruli may be associated with or may directly cause renal dysfunction. We tried to assess the influence of the -2578 C/A and -1154 G/A polymorphisms in the regulatory region of the vascular endothelial growth factor gene upon progression of three primary chronic glomerulonephritides (minimal change disease/focal and segmental glomerulosclerosis, membranous nephropathy, immunoglobulin A nephropathy). We studied a cohort of 213 patients compared to 311 unrelated healthy controls. Analysis of the C/A polymorphism of vascular endothelial growth factor revealed an increased prevalence of CC genotype in the minimal change disease/focal and segmental glomerulosclerosis group in comparison with the other groups. A balanced distribution of G and A alleles among the respective types of chronic glomerulonephritides was shown in the analysis of -1154 G/A polymorphism. Finally, we have not proved any significant influence of the polymorphisms at positions -2578 C/A and -1154 G/A of the vascular endothelial growth factor gene promoter on the progression of chronic glomerulonephritides even though our study suggests a negative effect of CC genotype of -2578 C/A polymorphism on the clinical course of minimal change disease/focal segmental glomerulosclerosis.

DNA analysis of renal electrolyte transporter genes among patients suffering from Bartter and Gitelman syndromes: summary of mutation screening.

Patients with renal diseases associated with salt-losing tubulopathies categorized as Gitelman and classic form of Bartter syndrome have undergone genetic screening for possible mutation capture in two different genes: SLC12A3 and CLCNKB. Clinical symptoms of these two diseases may overlap. Patients with clinical symptoms of antenatal form of Bartter syndrome were screened for mutations in two different genes: KCNJ1 and SLC12A1. The aim was to establish genetic mutation screening of Bartter/Gitelman syndrome and to confirm the proposed diagnosis. We have identified seven different causative mutations in the SLC12A3 gene, four in the CLCNKB gene, two in the SLC12A1 gene, and none in the KCNJ1 gene. Nine of these mutations are novel. In one case, genetic analysis led to re-evaluation of diagnosis between the Gitelman and classic form of Bartter syndrome.

Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.

Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.(ClinicalTrials.gov identifier: NCT00976300)

[Systemic amyloidoses in renal biopsy samples]. / Systémové amyloidózy v biopsiích ledvin.

UNLABELLED: The kidneys are one of the most frequent sites of amyloid deposition during systemic AL, AA, and several hereditary amyloidoses. Distinguishing between different forms of amyloids is clinically important because of their different treatment. MATERIAL AND METHODS: We present a 5-year retrospective study of amyloidoses diagnosed in renal biopsy samples. The classification of amyloidosis was made by immunofluorescence and immunohistochemical staining with antibodies to kappa and lambda immunoglobulin light chains, and for serum amyloid A protein. RESULTS: From January 2003 to December 2007, 996 renal biopsy samples from one centre were evaluated. Amyloidosis was diagnosed in 62 samples (6.2%); 33 (53.2%) were classified as AL and 25 (40.3%) as AA amyloidosis. Four cases have remained unclassified. We did not identify any difference in the distribution of deposits among cases with AL and AA amyloidosis, respectively. The majority of patients underwent the renal biopsy due to severe proteinuria or nephrotic syndrome. Three patients had very low proteinuria, less than 0.5 g/day. Diagnosis of amyloidosis was suspected by nephrologists in 48 patients (77.4%). CONCLUSION: Diagnosis of amyloidosis involves detection of amyloid deposits and classification of the amyloid form, which represent the basic step for appropriate therapy. Altogether it is not an easy task for pathologists, and with the emergence of markedly different treatments depending on the specific type of amyloid, the precise typing is of increasing clinical importance and should be performed with great care. Immunofluorescence can be very useful in daily practice for classification of the type of amyloidosis.

Renal AA amyloidosis: survey of epidemiologic and laboratory data from one nephrology centre.

Renal amyloid involvement results, especially, from AL (primary) or AA (secondary) amyloidosis. The extent of amyloid tissue deposits in the kidneys and the clinical course of amyloidosis not only depend on the type of basic process but also reflect the time of diagnosis and the ability to affect the underlying disease. We analyzed laboratory and clinical data from patients with bioptically proven renal amyloidosis. Renal amyloidosis was found in 99 patients (4.65%) from an overall number of 2,128 renal biopsies (RB) performed in our department during a period of 11 years (from 1995 to 2006). AA amyloidosis was diagnosed in 46 patients. Nephrotic syndrome was diagnosed in 27 patients (59%) with AA amyloidosis; all these patients had different degrees of proteinuria. Impaired renal function was discovered in 24 patients (52%); in three of these patients (6.5%) we had to start renal replacement therapy. Patients were treated with corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biological therapy in various regimens. Nine patients (19.5%) died during the one-year follow-up period; complications such as sepsis and cardiac failure were the leading causes of death. Median survival in the AA group was 54 months. Although for approximately half of patients different treatment regimens can lead to a partial remission or disease stabilization, the prognosis of patients with amyloidosis could be regarded as unsatisfactory.

T cells in the pathogenesis of ANCA-associated vasculitis: current knowledge.

AAV are a group of systemic immune-mediated diseases with a strong and highly specific association with ANCA. In recent years, there has been increasing evidence that ANCA might play a direct pathogenic role in triggering AAV. Nevertheless, effectors of cell-mediated immunity prevail in the inflammation sites in patients with AAV. Numerous studies found increased markers of T-cell activation in AAV. Moreover, this activation persisted even in remission and despite treatment. Finally, successful therapeutic attempts using T cell-directed treatment were also reported. There has therefore been substantial evidence that T cells are involved in the pathogenesis of AAV, even though the exact mechanisms are yet to be elucidated. In this review, recent findings on the contribution of T cells to the pathogenic processes in AAV will be briefly summarized. Special emphasis will be placed on the Th1/Th2 concept, the role of T-regulatory cells, and the role of effector memory T cells in the pathogenesis of AAV.

The influence of two megsin polymorphisms on the progression of IgA nephropathy.

The clinical course of chronic renal diseases and their progression to ESRD is highly variable. The strongest predictors of poor outcome of IgAN involve hypertension, severe proteinuria and elevated serum creatinine level. Different candidate gene polymorphisms have been advocated as possible modulators of the progression of IgAN. Megsin belongs to the serpin superfamily and was mapped to chromosome 18q21.3. Megsin plays a role in the regulation of a wide variety of processes in mesangial cells, such as matrix metabolism, cell proliferation, and apoptosis. Overexpression of Megsin might lead to mesangial dysfunction, and impair degradation of the mesangial matrix and disposal of immune complexes. The expression of Megsin is upregulated in a variety of glomerular diseases with mesangial injury in humans and in animal models. We investigated a possible association of two C2093T, C2180T polymorphisms of the megsin gene with the progression of IgAN towards ESRD, as well as the haplotype reconstruction of megsin gene polymorphisms and clinical manifestation of IgAN. We examined a group of 197 pts with histologically proven IGAN (84 pts with normal renal function, 113 pts with progressive renal insufficiency); as a control group we used 61 genetically unrelated healthy subjects. DNA samples from collected blood were genotyped for two singlenucleotide polymorphisms of megsin C2093T, C2180T by means of PCR with defined primers, electrophoresis on 2% agarose gel, UV light visualization and direct sequencing. The megsin genotype distribution showed no differences among the groups of IgAN with normal renal function, progressive renal insufficiency and the control group. According to haplotype analysis, the TT haplotype (defined as T-2093, T-2180 alleles) was substantially more frequent in pts with IgAN and normal renal function (Table 1, P = 0.025; Table 3, P = 0.062). Pts in the progressive group showed significantly higher levels of 24-h UP (3.53 +/- 2.80 vs 2.06 +/- 2.06, P = 0.042; Table 10), diastolic blood pressure (92.89 +/- 15.66 vs 84.93 +/- 10.43, P = 0.047; Table 10) and almost significantly systolic blood pressure (150.79 +/- 32.88 vs 135.21 +/- 14.88, P = 0.058; Table 10). We confirmed the negative prognostic influence of hypertension and proteinuria on the progression of IgAN in Czech pts. We found out that the TT haplotype (defined as T-2093, T-2180 alleles) could play a protective role in the progression of IgAN. In our Czech population, we excluded the negative influence of the 2093C-2180T haplotype, which was proposed by Chinese studies.

The influence of three endothelin-1 polymorphisms on the progression of IgA nephropathy.

The clinical course of chronic renal diseases and their progression to ESRF is highly variable. Different candidate gene polymorphisms have been advocated as possible modulators of ESRF progression. Moreover, ET-1 has been suggested as a major promoting factor in renal disease. However, limited data are available regarding an association of three ET-1 SNP K198N, T- 1370G and 3A/4A with the progression of IgAN to ESRF. We examined a group of 122 pts with histologically proved IgAN (91 pts with normal renal function, 31 pts with ESRF), as a control group we used 132 genetically unrelated healthy subjects. Patients' DNAs were genotyped for three ET-1 SNP: K198N, T-1370G and 3A/4A by means of PCR. The frequencies of different genotypes and ET-1 gene haplotypes were compared among control group, IgAN pts with normal renal function and IgAN pts with ESRF. The ET-1 genotype distribution showed no differences among the groups of IgAN with normal renal function (1. K198N - 63.74% KK, 32.97% KN, 3.3% NN; 2. TT - 68.13% TT, 28.57% TG, 3.3% GG; 3. 3A/4A - 42.22% 3A/3A, 50.0% 3A/4A, 7.69% 4A/4A ), IgAN with ESRF (1. K198N - 74.19% KK, 25.81% KN, 0% NN; 2. TT - 77.42% TT, 22.58% TG, 0% GG, 3. 3A/4A - 56.25% 3A/3A, 37.5% 3A/4A, 6.25% 4A/4A ) and the control group (1. K198N - 66.67% KK, 31.82% KN, 1.52% NN, 2. TT - 76.51% TT, 22.72% TG, 0.76% GG, 3. 3A/4A - 43.94% 3A/3A, 44.70% 3A/4A, 11.36% 4A/4A ). The analysis of haplotypes showed that the frequency of G-198, G-1370 and 4A allele combination was significantly higher in comparison with the control group (P=0.0056). We excluded the effect of K198N, T-1370G and 3A/4A polymorphisms of the ET-1 gene in single-gene analysis on the progression of IgAN to ESRF. A significant association of the GG4A haplotype with IgAN, demonstrated by haplotype reconstruction of the ET-1 gene, could suggest a role in the pathogenesis of IgAN.

Long-term outcome of patients with idiopathic membranous nephropathy.

Although idiopathic membranous nephropathy (iMN) is a common glomerular disease, its therapy still remains controversial. The aim of our study was to analyse the outcome of patients with iMN diagnosed and treated in our center. We retrospectively studied 82 patients with iMN that were diagnosed between January 1991 and June 2002. The group consisted of 57 males (69.5%) and 25 females (30.5%) with a mean age of 53 years. The mean follow-up was 56 +/- 38 months. Remission was achieved in 59.2% of patients treated with chlorambucil, 71.4% treated with cyclophosphamide, 85.7% treated with cyclosporine and in 71.4% of those who were left untreated intentionally. However, the proportion of patients in the different treatment subgroups differed significantly (60% vs. 8.5% vs. 8.5% vs. 23%, respectively). The relapse rate was 31.3%. The second-line treatment was effective in a majority of the patients. At the end of follow-up, almost 70% of the patients were in remission with the parameters of nephrotic syndrome significantly improved and renal function unchanged. The renal survival was 100%. Immunosuppressive therapy is effective in iMN, but spontaneous remissions occur as well. Although relapses are frequent, almost 70% of the patients were in remission at the end of follow-up. The renal survival in our group of iMN patients was very good, probably due to preserved renal function at diagnosis.

The pathogenetic aspects and gene polymorphisms of IgA nephropathy.

Immunoglobulin A nephropathy is an immune-complex-mediated glomerulonephritis characterized by diffuse mesangial deposition of immunoglobulin A or IgA--containing immune complexes. Although its most common clinical presentation is macroscopic hematuria provoked by upper respiratory tract infection, this is neither universal nor necessary for the diagnosis. The patients with IgA nephropathy manifest with variable clinical symptoms (e.g., microhematuria with preserved renal function or progressive deterioration of renal functions resulting in end-stage renal disease). The pathogenetic mechanisms include the abnormality of O-glycosylation of the IgA1 molecule, genetic factors, environmental factors and various inflammatory mediators. The source of mesangial IgA deposits is total circulating serum IgA but the response of the mesangium and the mesangial cells to the deposited IgA is critical to the development of IgAN. Without a genetic predisposition to IgAN, IgA deposition can cause no risk for triggering glomerulonephritis. If generic progression risk factors of an unfavourable outcome coincide (e.g. hypertension, severe proteinuria, elevated serum creatinine level), this will increase the likelihood of progressive renal impairment. Further studies are needed to disclose the precise pathogenetic mechanisms involved in primary IgA nephropathy and to facilitate the development of newer therapeutic possibilities.