Hematological and immunological development from birth to six months of age in Holstein calves / Desenvolvimento hematológico e imunológico em bezerros Holandeses do nascimento aos seis meses de idade

The hematological and immunological development of calves from birth to 6 months of age was performed by hemogram and cellular phenotype. Ten male Holstein calves were assessed in 13 moments: before colostrum intake (D0), every 2 days until the 10th day of life (D2 to D10), at the 15th day after birth (D15), and then monthly up to 6 months (D180). Calves presented hemoconcentration on day (D) 0 and showed a gradual decrease in hematimetric rates until D180. The inversion of the neutrophilic for lymphocytic profile was observed on D4. The percentage of CD3+ cells on D10 was higher than D30 up to D180. The number of CD4+ and CD8+ cells did not change between time points. The number of CD21+ lymphocytes was significantly higher at early time points of D0 up to D15, compared on D30 until D150. In conclusion, the neonatal period was marked by stress leukogram in the first 4 days, and low number of B lymphocytes. These might be risk factors for bacterial infections responsible for navel inflammation and diarrhea. The increase in the number of B cells from 30 days of age demonstrated that the calves were functional and able to generate an immune response.(AU)

O desenvolvimento hematológico e o imunológico de bezerros do nascimento aos seis meses de idade foram avaliados por meio hemograma e imunofenotipagem dos linfócitos. Para tanto, 10 bezerros machos Holandeses foram avaliados em 13 momentos: antes da ingestão do colostro (D0), a cada dois dias até o 10º dia (D2 a D10), 15º dia (D15) e, em seguida, mensalmente até seis meses de idade (D180). Os bezerros apresentaram hemoconcentração em D0 e decréscimo gradual dos índices hematimétricos até D180. A inversão do perfil neutrofílico para linfocítico foi observada em D4. Os valores de CD3+ (%) em D10 foram maiores que aqueles observados em D30 até D180. CD4+ e CD8+ não apresentaram alterações entre os momentos. Os linfócitos B CD21+ aumentaram significativamente a partir dos primeiros momentos D0 até D15, em comparação com os momentos subsequentes D30 até D150. Em conclusão, o período neonatal foi caracterizado pelo leucograma de estresse nos primeiros quatro dias e o baixo número de linfócitos B. Esses fatos podem ser considerados como fatores de risco para infecções bacterianas responsáveis pelas inflamações umbilicais e pela diarreia. Por outro lado, o aumento de células B após os 30 dias de vida demonstrou que os bezerros foram capazes de gerar uma resposta imune.(AU)

Bovine papillomavirus in Brazil: detection of coinfection of unusual types by a PCR-RFLP method.

Bovine papillomavirus (BPV) is recognized as a causal agent of benign and malignant tumors in cattle. Thirteen types of BPV are currently characterized and classified into three distinct genera, associated with different pathological outcomes. The described BPV types as well as other putative ones have been demonstrated by molecular biology methods, mainly by the employment of degenerated PCR primers. Specifically, divergences in the nucleotide sequence of the L1 gene are useful for the identification and classification of new papillomavirus types. On the present work, a method based on the PCR-RFLP technique and DNA sequencing was evaluated as a screening tool, allowing for the detection of two relatively rare types of BPV in lesions samples from a six-year-old Holstein dairy cow, chronically affected with cutaneous papillomatosis. These findings point to the dissemination of BPVs with unclear pathogenic potential, since two relatively rare, new described BPV types, which were first characterized in Japan, were also detected in Brazil.

High density lipoprotein cholesterol levels are an independent predictor of the progression of chronic kidney disease.

OBJECTIVES: Patients with chronic kidney disease (CKD) often present with reduced plasma HDL cholesterol (HDL-C) levels. Whether this reduction in an epiphenomenon or is involved in disease progression is unclear. The aim of this study was to investigate the relation between HDL-C levels/function and CKD progression in patients with different degrees of disease. DESIGN: A total of 176 patients with CKD [glomerular filtration rate (GFR) 50.3 ± 29.1 mL min⁻¹] were recruited and followed for up to 84 months. Lipid profile, metabolic status and kidney function were evaluated at predetermined times. Age-matched control subjects were selected from the PLIC study (n = 453). Scavenger receptor class B member 1 (SR-BI) and ATP-binding cassette transporter A1 (ABCA-1)-dependent efflux of cholesterol were measured in CKD patients and in age-matched control subjects. RESULTS: Low HDL-C levels, diabetes and hypertension were associated with reduced GFR. At follow-up, low HDL-C levels were associated with earlier entry in dialysis or doubling of the plasma creatinine level (P = 0.017); HDL-C levels were the only lipid parameter that affected the progression of CKD (hazard ratio 0.951, 95% confidence interval 0.917-0.986, P = 0.007), independently of the presence of diabetes. Only SR-BI-mediated serum cholesterol efflux was significantly reduced in the group of CKD patients with low HDL-C levels compared to the control group. CONCLUSIONS: CKD patients with low levels of plasma HDL-C have a poor prognosis. HDL functionality is also impaired in renal dysfunction. These data support the relevance of HDL in influencing CKD progression.

Expression profiling of genes involved in the formation of aroma in two peach genotypes.

The expression profile of flavour-related genes during ripening was investigated in two peach genotypes, Bolero and OroA, which have been selected for their contrasting aroma/ripening behaviour. A new peach microarray containing 4776 oligonucleotide probes corresponding to a set of ESTs specifically enriched in secondary metabolism (µPEACH2.0) was designed to investigate transcriptome changes during three fruit ripening stages, revealing 1807 transcripts differentially expressed within and between the two genotypes. Differences in the expression of genes involved in the biosynthesis of aroma compounds were detected during the ripening process within and between the two genotypes. In particular, a subset of 12 transcripts involved in metabolism of esters, norisoprenoids, phenylpropanoids and lactones, varied in expression during ripening and between Bolero and OroA.

Excretion of Brucella abortus vaccine B19 strain during a reproductive cycle in dairy cows

This paper aimed to determine the excretion period of B19 vaccine strain during a complete reproductive cycle (from estrus synchronization, artificial insemination, pregnancy and until 30 days after parturition) of dairy cows from 3 to 9 years old that were previously vaccinated from 3 to 8 months. Three groups were monitored with monthly milk and urine collection during 12 months: G1 with seven cows from 3 to 4 years old; G2 with three cows from 5 to 6 years old; and G3 with four cows from 7 to 9 years old. Urine and milk samples were submitted to bacteriological culture and urine and PCR reactions for detection of Brucella spp. and PCR-multiplex for B19 strain identification. Ring test (RT) was also performed in the milk samples, and serum samples were tested by buffered acidified plate antigen test (BAPA). All animals were serologically negative at BAPA and Brucella spp. was not isolated from both urine and milk samples. RT revealed 13/210 (6.2%) positive milk samples. PCR reactions detected DNA of Brucella spp. in 86/420 (20.5%) samples. In urine it was found a significantly higher frequency (35.2%; 74/210) than in milk (5.7%; 12/210), more frequently from the estrus to 150 days of pregnancy and after parturition (6.7%; 10/150), and from 150 days of pregnancy to parturition (3.4%; 2/60), and they were all identified as B19 strain. In three groups, intermittent excretion of B19 strain was detected mainly in urine samples, which confirmed its multiplication and persistence in cows for until 9 years.

Excretion of Brucella abortus vaccine B19 strain during a reproductive cycle in dairy cows.

This paper aimed to determine the excretion period of B19 vaccine strain during a complete reproductive cycle (from estrus synchronization, artificial insemination, pregnancy and until 30 days after parturition) of dairy cows from 3 to 9 years old that were previously vaccinated from 3 to 8 months. Three groups were monitored with monthly milk and urine collection during 12 months: G1 with seven cows from 3 to 4 years old; G2 with three cows from 5 to 6 years old; and G3 with four cows from 7 to 9 years old. Urine and milk samples were submitted to bacteriological culture and urine and PCR reactions for detection of Brucella spp. and PCR-multiplex for B19 strain identification. Ring test (RT) was also performed in the milk samples, and serum samples were tested by buffered acidified plate antigen test (BAPA). All animals were serologically negative at BAPA and Brucella spp. was not isolated from both urine and milk samples. RT revealed 13/210 (6.2%) positive milk samples. PCR reactions detected DNA of Brucella spp. in 86/420 (20.5%) samples. In urine it was found a significantly higher frequency (35.2%; 74/210) than in milk (5.7%; 12/210), more frequently from the estrus to 150 days of pregnancy and after parturition (6.7%; 10/150), and from 150 days of pregnancy to parturition (3.4%; 2/60), and they were all identified as B19 strain. In three groups, intermittent excretion of B19 strain was detected mainly in urine samples, which confirmed its multiplication and persistence in cows for until 9 years.

Conformational preference of chlorothioformate species: molecular structure of ethyl chlorothioformate, ClC(O)SCH2CH3, in the solid phase and NBO analysis.

The molecular structure of ethyl chlorothioformate, ClC(O)SCH(2)CH(3), has been investigated in the solid phase by X-ray diffraction analysis at low temperature using a miniature zone-melting procedure and IR laser radiation. The crystalline solid consists exclusively of molecules with the synperiplanar conformation with respect to the C=O double bond and the S-C single bond, and gauche orientation of the ethyl group (syn-gauche). These results coincide with previous studies devoted to gas-phase conformational properties. The conformational preference for the ClC(O)SY (Y = Cl, CF(3), CH(3) and CH(2)CH(3)) series of molecules was rationalized using the natural bond orbital (NBO) scheme. It was found that both resonance (mesomeric) and anomeric (hyperconjugation) intermolecular charge-transfer interactions are important for describing the syn ↔ anti equilibrium, also illustrating the effect of electronegativity of the substituent in the conformation preference of the ClC(O)S- moiety. On the basis of the atoms in molecules (AIM) theory, intermolecular interactions have been characterized in the B3LYP/6-31G** periodic boundary electron density.

Is suboptimal prescribing a risk factor for poor health outcomes in community-dwelling elders? The ICARe Dicomano study.

PURPOSE: Mostly because of comorbidity and drugs consumption, older persons are often exposed to an increased risk of sub-optimal prescribing (SP). At present, few studies investigated the association between SP and long-term health outcomes. We examined the relation between SP and the risk of mortality and hospitalization in Italian older community-dwellers. METHODS: Older (65+ years) community-dwelling residents of a small town in Tuscany were enrolled in a longitudinal study. SP was defined as polypharmacy (use of 5+ drugs), prescription of inappropriate drugs (ID) according to Beers' criteria, and of potentially interacting drugs (PID), evaluated in 1995 and 1999. These three forms of SP were entered as time-dependent exposures into multivariable Cox regression analysis models, whose outcomes were mortality and hospitalizations through 2003. RESULTS: Of 1022 participants (mean age 73.0 +/- 6.8, 57% women), 220 were evaluated in 1995, 234 in 1999 and 568 in both waves. In univariate analysis, mortality was two-fold higher in participants with polypharmacy (73.4/1000 person/years, 95% CI 58.2-92.4 vs. 34.1, 95% CI 29.7-39.2; p < 0.001) or PID (72.7/1000 person/years, 95% CI 46.3-113.9 vs. 38.0, 95% CI 33.5-43.1; p < 0.001), whereas it was unrelated to the presence of ID. Hospitalization rates were independent of any form of SP. In multivariable models, polypharmacy, ID, and PID were no longer associated with an increased risk of death, and ID predicted a slightly increased risk of hospitalizations (HR 1.03, 95% CI 1.0-1.06, p = 0.048). CONCLUSIONS: In this cohort, SP was not associated with an excess risk of poor health outcomes.

CK2 and GSK3 phosphorylation on S29 controls wild-type ATXN3 nuclear uptake.

In the present work we show that murine ATXN3 (ATXN3Q6) nuclear uptake is promoted by phosphorylation on serine 29, a highly conserved residue inside the Josephin domain. Both casein kinase 2 (CK2) and glycogen synthase kinase 3 (GSK3) are able to carry out phosphorylation on this residue. S29 phosphorylation was initially assessed in vitro on purified ATXN3Q6, and subsequently confirmed in transfected COS-7 cells, by MS analysis. Site-directed mutagenesis of S29 to an alanine was shown to strongly reduce nuclear uptake, in COS-7 transiently transfected cells overexpressing ATXN3Q6, while substitution with phospho-mimic aspartic acid restored the wild-type phenotype. Finally, treatment with CK2 and GSK3 inhibitors prevented S29 phosphorylation and strongly inhibited nuclear uptake, showing that both kinases are involved in ATXN3Q6 subcellular sorting. Although other authors have previously addressed this issue, we show for the first time that ATXN3 is phosphorylated inside the Josephin domain and that S29 phosphorylation is involved in nuclear uptake of ATXN3.

On the electron density topology and electrostatic properties of nitroanilines. A theoretical investigation on m-nitroaniline and 2-methyl-5-nitroaniline crystals.

On the basis of the AIM theory, intermolecular interactions have been characterized in the B3LYP/6-31G** periodic electron density of the title compounds. Although the set of bond paths identified in each system is not fully equivalent to its experimental counterpart, agreement is reasonable with regard to the nature and relative importance of the intermolecular interactions at play. Within the AIM partition scheme, the molecular dipole moment of the in-crystal molecule was determined for the title compounds and the two closely related crystals of 2-methyl-4-nitroaniline and p-nitroaniline. Using a method that relies only on molecular calculations and a mean electric field approximation, it was possible to reproduce within 6% the values of the molecular dipole moment modulus obtained directly from the periodic electron densities. This result reveals that, for this kind of molecular crystal, enhancement of the dipole moment in going from the isolated molecule to the in-crystal one is an almost exclusively inductive effect.

[The role of steroids in the treatment of IgA nephropathy]. / Gli steroidi nella terapia della nefropatia a depositi IgA.

IgA nephropathy (IgAN) is characterized by a variable natural history. Welldefined risk factors from a clinical point of view are renal function impairment, associated hypertension, and proteinuria, while tubular-interstitial fibrosis constitutes a histological risk factor. These are serious clinical symptoms and histological signs, indicating long-lasting and severe damage. The available therapeutic tools belong essentially to two categories: 1) angiotensin inhibitors and 2) steroids, associated or not with immunosuppressive drugs. ACE inhibitors have limited toxicity and no significant side effects, and nephrologists are inclined to use them in case of moderate proteinuria. Steroids, in some cases associated with immunosuppressive agents, are obviously more demanding for the patient. Decisions must be made by the clinicians regarding the timing and the possible presence of contraindications. Furthermore, the treatment may not yield the expected results and a critical approach by the nephrologist is necessary. This controversy highlights the theoretical and practical issues related to steroid therapy in IgAN and here we discuss the different approaches to indications, doses, duration and route of administration.

Effects of gamma-radiation on the fungus Alternaria alternata in artificially inoculated cereal samples.

The objective of this study was to evaluate the effects of different gamma-radiation doses on the growth of Alternaria alternata in artificially inoculated cereal samples. Seeds and grains were divided into four groups: Control Group (not irradiated), and Groups 1, 2 and 3, inoculated with an A. alternata spore suspension (1 x 10(6) spores/mL) and exposed to 2, 5 and 10 kGy, respectively. Serial dilutions of the samples were prepared and seeded on DRBC (dichloran rose bengal chloramphenicol agar) and DCMA (dichloran chloramphenicol malt extract agar) media, after which the number of colony-forming units per gram was determined in each group. In addition, fungal morphology after irradiation was analyzed by scanning electron microscopy (SEM). The results showed that ionizing radiation at a dose of 5 kGy was effective in reducing the growth of A. alternata. However, a dose of 10 kGy was necessary to inhibit fungal growth completely. SEM made it possible to visualize structural alterations induced by the different gamma-radiation doses used.

[Treatment of IgA nephropathy with chronic renal failure]. / Il trattamento della nefropatia a depositi di IgA con insufficienza renale cronica.

INTRODUCTION: About 25-50% of patients with IgA nephropathy (IgAN) progress toward end-stage renal disease (ESRD) within 25 years. Negative prognostic factors are hypertension, proteinuria >1 g/day, high values of plasma creatinine, and the extension of chronic histological lesions. METHODS AND RESULTS: Only a few studies have evaluated the effectiveness of treatment in IgAN patients with chronic renal failure (CRF) and most of these had methodological flaws. However, some studies produced interesting results. Alexopoulos and Donadio found that the progression of IgAN slowed down with the use of omega-3 fatty acids; Woo and Nakao used angiotensin inhibitors to obtain the same result, while Ballardie used immunosuppressors. Evidence of treatment efficacy in chronic histological lesions is almost completely lacking. Yoshikawa found that a two-year course of corticosteroids and azathioprine could arrest the progression of glomerular sclerosis, and Shoji obtained similar results using corticosteroids alone for one year. In 2007 we presented the results of a study that compared corticosteroids alone vs corticosteroids and azathioprine in 253 IgAN patients. In all patients, including 46 with serum creatinine >2 mg/dL, both therapy schemes appeared effective in slowing the progression towards ESRD, even if patients in the azathioprine group experienced more side effects. CONCLUSIONS: At the moment, Italian nephrologists preferably use ACE inhibitors alone or associated with corticosteroids in patients with IgAN and CRF. Recently, the Renal Immunopathology Group of the Italian Society of Nephrology (SIN) proposed a therapeutic study that would compare steroids and ACE inhibitors in patients with IgAN and CRF in order to provide more certain therapeutic indications.

The long-term prognosis of renal transplant in patients with systemic vasculitis.

Little information is available about the long-term outcome of renal transplantation in patients with systemic vasculitis (SV). We compared the outcomes of 19 renal transplant recipients with SV with those of 38 controls matched for time of transplantation, age, gender and source of donor. The mean post-transplant follow-up was 58 +/- 57 months for vasculitic patients and 61 +/- 49 months for controls. The actuarial 10-year patient survival was 87% in vasculitic patients and 90% in controls, death-censored graft survival were 84% and 100%, respectively. The risks of acute and chronic rejection, and arterial hypertension were not significantly different between the two groups. Infection was significantly more frequent in vasculitic patients (74% vs. 34%; p = 0.01). Seven patients (36.8%) had a recurrence of vasculitis in mean 45 months after renal transplant (0.076/patients/year). After recurrence, one patient had an irreversible humoral rejection, another died from hemophagocytosis and another restarted dialysis 1 year later. Long-term patient and renal allograft survival in vasculitic patients was good. Although graft function recovered in most relapsers after reinforcement of immunosuppression, one patient died and two lost graft function.

[Therapeutic strategies for membranous nephropathy: guideline from the Italian Society of Nephrology]. / Terapia della nefropatia membranosa idiopatica: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of interventions for idiopathic membranous nephropathy (MN) is presented. METHODS: SR of RCT and RCT on interventions for MN were identified referring to a Cochrane Library and Renal Health Library search (2005 update). RESULTS: Three SR and 18 RCT were available to address this issue. Methodological quality of available RCT was suboptimal according to current methodological standards. In patients with MN, nephrotic syndrome and normal renal function, methylprednisolone and chlorambucil or cyclophosphamide for 6 months alternately increase the probability of nephritic syndrome remission (evidence from SR) and long-term renal protection (evidence from RCT). Other drugs (ACTH and cyclosporine) are associated with nephrotic syndrome remission, but there is no evidence of significant effects on renal function (evidence from RCT). In patients with impaired renal function, association of corticosteroids and cytotoxic agents is proven to cause a short-term delay of renal damage progression, even though benefits are counterbalanced by complications (evidence from RCT). CONCLUSION: In patients with MN, nephrotic syndrome and normal renal function, current available evidence supports the hypothesis that primary intervention should be the association of corticosteroids and cytotoxic agents. Secondary therapeutic choices include ACTH and cyclosporine. Further studies are necessary to test new immunosuppressive agents such as mycophenolate mofetil.

[Corticosteroid treatment for a first episode of steroid-sensitive nephrotic syndrome (SSNS) in children: guideline from the Italian Society of Nephrology]. / Terapia corticosteroidea del primo episodio di sindrome nefrosica steroido-sensitiva nel bambino: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the use of corticosteroid treatment for a first episode of steroid-sensitive nephrotic syndrome (SSNS) in children is presented. METHODS: SR of RCT and RCT on SSNS therapeutic interventions were identified referring to a Cochrane Library and Renal Health Library search (2005 update). Results. One SR including 15 RCT was available on this topic. Methodological quality of available RCT was suboptimal according to current methodological standards. RESULTS: In children with a first episode of SSNS, corticosteroids administered for 3 months or more compared with 2 months' administration are associated with a significant reduction in the risk of relapse at 6, 12 and 24 months, and in frequent relapsing rates, even though complications did not seem significantly increased (psychological, ocular, gastrointestinal disorders, hypertension, growth delay, Cushingoid syndrome, infection and osteoporosis) (evidence from SR). 6-month compared to 3-month treatment regimens are associated with a significant reduction in the risk of relapse at 12-24 months (evidence from SR). Increasing steroids cumulative doses are associated with increasing improvements in the risk of relapse (evidence from RCT). The risk of relapse at 12-24 months correlates inversely with duration of treatment (evidence from SR). CONCLUSION: In SSNS children, current available evidence supports the hypothesis that primary intervention should be a high dose of corticosteroids administered for 3 months or more. Further studies are necessary to test this hypothesis in adult patients.

[Immunosuppressive and non-immunosuppressive agents for patients with IgA nephropathy: guideline from the Italian Society of Nephrology]. / Terapia immunosoppressiva e non immunosoppressiva della glomerulonefrite a depositi mesangiali di IgA: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the use of immunosuppressive and non-immunosuppressive treatments in IgA nephropathy (IgAN) is presented. METHODS: SR of RCT and RCT on treatment in patients with IgAN were identified referring to a Cochrane Library and Renal Health Library search (2005 update). Quality of SR and RCT was assessed according to current methodological standards. RESULTS: Two SR of RCT (13 and 3 RCT, respectively), and 18 further RCT were available to address this issue. Methodological quality of available trials was suboptimal. In patients with IgAN and normal or mildly impaired renal function, steroids significantly delay the progression to end stage kidney disease (evidence from SR) and improve proteinuria. Associating steroids and cytotoxic agents (cyclophosphamide followed by oral azathioprine) proves effective in patients with rapidly progressive renal disease (evidence from RCT). Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers significantly improve proteinuria (evidence from RCT), but there are no conclusive data on efficacy on hard patient level endpoints. There are no conclusive data available on the use of a therapy combining these agents. CONCLUSION: In IgAN patients current evidence supports the hypothesis that immunosuppressive agents delay the progression to end stage renal disease. Further studies are necessary to test this hypothesis in selected patient populations.

[Treating lupus nephritis: guideline from the Italian Society of Nephrology]. / Terapia delle nefriti proliferative lupiche; confronto degli schemi di associazione di farmaci citotossici più steroide rispetto al solo steroide: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of lupus nephritis (LN) treatment is presented. METHODS: SR of RCT and RCT on different therapeutic options for LN were identified referring to a Cochrane Library and Renal Health Library search (2005 update). RESULTS: One SR of 25 RCT and 6 further RCT were available to address this issue. Methodological quality of available RCT was suboptimal according to current methodological standards. In LN patients, combining cyclophosphamide (CyA) and steroids as induction therapy results in a reduced risk of serum creatinine doubling compared to steroids alone, although there is no evidence of significant survival advantage and risk of ovarian failure was demonstrated (evidence from SR). The association of azathioprine (Aza) and steroids significantly reduces the risk of all-cause mortality compared to steroids alone (evidence from SR). No significant survival advantages from the association of plasma exchange and CyA or Aza are proven (evidence from SR). No significant differences on renal and survival endpoints are demonstrated with different dosing of CyA (evidence from RCT). CONCLUSION: In LN patients available evidence supports the hypothesis that immunosuppressive agents reduce the risk of all-cause mortality and the risk of progressive renal disease. Further studies are necessary to test new immunosuppressive agents such as mycophenolate mofetil in severe LN patients.