Evidence that two independent host genes influence the severity of tissue damage and susceptibility to acute pyelonephritis in murine systemic candidiasis

Tissue damage in the kidney and brain after systemic infection with Candida albicans was examined in recombinant inbred strains (AKXL) derived from AKR and C57/L progenitors. Nine of the 15 strains showed mild (C57/L-like) tissue damage. Of the remainder, two strains developed lesions comparable to the AKR parental strain, whereas four exhibited a much move severe pattern of tissue damage. This was characterized by pronounced mycelial growth in the brain, and gross oedema of the kidney, with extensive fungal colonization and marked tissue destruction. The presence of the null allele of the haemolytic complement gene (Hc) may be necessary but not sufficient, for the expression of the very severe lesions. The results were interpreted as reflecting the actions of two independent genes, which have been designated Carg1 and Carg2 (Candida albicans resistance genes 1 and 2). (C) 1997 Academic Press Limited.

Menstrual and hormonal alterations in juvenile systemic lupus erythematosus

Menstrual cycles of 30 patients with juvenile systemic lupus erythematosus (JSLE) were compared with 30 age-matched controls. The mean age of patients with JSLE and controls was similar (17.4 +/- 3.2 vs 17.06 +/- 2.08 years, P = 0.66). The mean menarche age was higher in JSLE than controls (13.13 +/- 1.4 vs 11.56 +/- 1.5 years, P = 0.0008). On the contrary, the mean maternal menarche age was similar in both groups (P = 0.62). Menstrual abnormalities and longer length cycles were more frequently observed in JSLE than controls (63% vs 10%, P = 0.0001; 23% vs 0%, P = 0.0105, respectively). The median of follicle stimulating hormone was significantly higher in patients with JSLE compared with controls (4.6 vs 3.4 IU/L, P = 0.0207), and the median of progesterone was lower (32.5 vs 70 ng/mL, P = 0.0033). The median Of luteinizing hormone was lower in patients with JSLE with menstrual abnormalities versus normal cycles (2.9 vs 5.5 IU/L, P = 0.019) and both had a high percentage of decreased progesterone levels (63% vs 73%, P = 0.70). Our findings support the notion that menstrual disturbances are frequent and may be associated with pituitary dysfunction leading to a decreased progesterone production. We also reported that in spite of premature ovarian failure being a rare event in JSLE the follicular reserve seems to be low regardless of intravenous cyclophosphamide treatment. Lupus (2009) 18, 38-43.

Testicular Sertoli cell function in male systemic lupus erythematosus

Objective. To assess the testicular Sertoli cell function in male SLE patients. Methods. Thirty-four consecutive patients were prospectively selected to evaluate serum inhibin B. Clinical features, treatment, semen analysis, urological evaluation, testicular ultrasound, hormones and anti-sperm antibodies were determined. Results. Patients were subdivided into two groups: low serum inhibin B (Group 1, n = 8) and normal levels (Group 2, n 26). The median sperm concentration (P = 0.024), total sperm count (P = 0.023) and total motile sperm count (P = 0.025) were lower in Group 1. Inhibin B levels were positively correlated with sperm concentration (r = 0.343), total motile sperm count (r = 0.357), and negatively correlated with follicule-stimulating hormone (FSH) (r = 0.699) and luteinizing hormone (r = 0.397). The median serum inhibin B was lower in SLE patients treated with intravenous cyclophosphamide (IVCYC) compared with those without this therapy (P = 0.031). Further evaluation of the 26 SLE patients with normal inhibin B and FSH levels revealed that medians of inhibin B/FSH ratio were lower in SLE patients with oligozoospermia compared with normozoospermia (P = 0.004). This ratio was also lower in SLE patients treated with IVCYC than those without this therapy (P = 0.04). In contrast, inhibin B serum level alone did not discriminate the later group of patients (P = 0.12). Conclusions. This is the first study to identify a high frequency of testicular Sertoli cell dysfunction in male SLE associated with semen abnormalities. Further prospective studies are necessary to determine if inhibin levels and inhibin B/FSH ratio will be an earlier and useful marker of IVCYC toxicity in these patients.

HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN EXPRESSION ENHANCES THE MOUSE SURVIVAL RATE IN AN EXPERIMENTAL SYSTEMIC INFLAMMATION MODEL: A NOVEL ROLE FOR CETP

Mice expressing human cholesteryl ester transfer protein (huCETP) are more resistant to Escherichia coli bacterial wall LIPS because death rates 5 days after intraperitoneal inoculation of LIPS were higher in wild-type than in huCETP(+/-) mice, whereas all huCETP(+/+) mice remained alive. After LIPS inoculation, plasma concentrations of TNF-alpha and IL-6 increased less in huCETP(+/+) than in wild-type mice. LPS in vitro elicited lower TNF-alpha production by CETP expressing than by wild-type macrophages. In addition, TNF-alpha production by RAW 264.7 murine macrophages increased on incubation with LPS but decreased in a dose-dependent manner when human CETP was added to the medium. Human CETP in vitro enhanced the LIPS binding to plasma high-density lipoprotein/low-density lipoprotein. The liver uptake of intravenous infused C-14-LPS from Salmonella typhimurium was greater in huCETP(+/+) than in wild-type mice. Present data indicate for the first time that CETP is an endogenous component involved in the first line of defense against an exacerbated production of proinflammatory mediators.

Pregnancy outcome in juvenile systemic lupus erythematosus: A Brazilian multicenter cohort study

Objective. To determine pregnancy outcome and fetal loss risk factors in patients with juvenile systemic lupus erythematosus (JSLE). Methods. A total of 315 female patients with JSLE followed in 12 Brazilian pediatric rheumatology centers were consecutively selected. Menarche was observed in 298 (94.6%) patients. Patients` medical records were reviewed for pregnancy outcomes and demographic, clinical, and therapeutic data. Results. A total of 24 unplanned pregnancies occurred in 298 (8%) patients. The outcomes were 5 (21%) early fetal losses (prior to 16 wks gestation), 18 (75%) live births, and 1 (4%) death due to preeclampsia and premature birth. The frequencies of active diffuse proliferative glomerulonephritis, proteinuria >= 0.5 g/day, and arterial hypertension at the beginning of pregnancy were higher in pregnancies resulting in fetal losses than in live births [60% vs 5% (p = 0.02), 60% vs 5% (p = 0.02), 60% vs 5% (p = 0.02), respectively]. JSLE pregnancies with fetal losses had a significantly higher mean SLE Disease Activity Index 2000 (SLEDAI-2K) at the start of pregnancy compared with those with live births (9.40 +/- 7.47 vs 3.94 +/- 6.00; p = 0.049). Four pregnancies were inadvertently exposed to intravenous cyclophosphamide therapy for renal involvement despite contraceptive prescriptions, resulting in fetal loss in 3 (p = 0.02). In multivariate analysis only intravenous cyclophosphamide use at start of pregnancy (OR 25.50, 95% CI 1.72-377.93, p = 0.019) remained as an independent risk factor for fetal loss. Conclusion. We identified immunosuppressive therapy as the major contributing factor for fetal loss in JSLE, reinforcing the importance of contraception.

Systemic lupus erythematosus and ""lupus dyslipoproteinemia""

A growing body of evidences reinforces the close link between systemic lupus erythematosus (SLE) and atherosclerosis which is due to traditional and nontraditional risk factors for cardiovascular diseases. It is now recognized that SLE has a particular pattern of dyslipoproteinemia characterized by low HDL levels and increased triglycerides, which is aggravated by flares. Multiple mechanisms can induce an altered lipoprotein metabolism in SLE such as cytokines produced during systemic inflammation, autoantibodies and therapy. (C) 2007 Elsevier B.V. All rights reserved.

The influence of lean mass in trabecular and cortical bone in juvenile onset systemic lupus erythematosus

The aim of this study was to evaluate risk factors for low bone mineral density (BMD) and vertebral fractures, in juvenile systemic lupus (JSLE). Thirty-one consecutive patients with JSLE were compared with 31 gender- and age-matched healthy controls. BNID and body composition from all participants were measured using dual-energy X-ray absorptiometry. Vertebral fractures were defined as a reduction of >= 20% of the vertebral height for all patients. Lumbar spine and total femur BMD was significantly decreased in patients compared with controls (P = 0.021 and P = 0.023, respectively). A high frequency of vertebral fractures (22.58%) was found in patients with JSLE. Analysis of body composition revealed lower lean mass (P = 0.033) and higher fat mass percentage (P = 0.003) in patients than in controls. Interestingly, multiple linear regression using BMD as a dependent variable showed a significant association with lean mass in lumbar spine (R(2) = 0.262; P = 0.004) and total femur (R(2) = 0.419, P = 0.0001), whereas no association was observed with menarche age, SLE Disease Activity Index, Systemic Lupus International Collaborating Clinics/American College of Rheumatology, and glucocorticoid. This study indicates that low BMD and vertebral fractures are common in JSLE, and the former is associated with low lean mass, suggesting that muscle rehabilitation may be an additional target for bone therapeutic approach.

PPAR gamma expression is increased in systemic lupus erythematosus patients and represses CD40/CD40L signaling pathway

Systemic lupus erythematosus (SLE) is a heterogeneous disease involving several immune cell types and pro-inflammatory signals, including the one triggered by binding of CD40L to the receptor CD40. Peroxisome-proliferator activated receptor gamma (PPAR gamma) is a transcription factor with anti-inflammatory properties. Here we investigated whether CD40 and PPAR gamma could exert opposite effects in the immune response and the possible implications for SLE. Increased PPAR gamma mRNA levels were detected by real-time PCR in patients with active SLE, compared to patients with inactive SLE PPAR gamma/GAPDH mRNA = 2.21 +/- 0.49 vs. 0.57 +/- 0.14, respectively (p < 0.05) or patients with infectious diseases and healthy subjects (p < 0.05). This finding was independent of the corticosteroid therapy. We further explored these observations in human THP1 and in SLE patient-derived macrophages, where activation of CD40 by CD40L promoted augmented PPAR gamma gene transcription compared to non-stimulated cells (PPAR gamma/GAPDH mRNA = 1.14 +/- 0.38 vs. 0.14 +/- 0.01, respectively; p < 0.05). This phenomenon occurred specifically upon CD40 activation, since lipopolysaccharide treatment did not induce a similar response. In addition, increased activity of PPAR gamma was also detected after CD40 activation, since higher PPAR gamma-dependent transcription of CD36 transcription was observed. Furthermore, CD40L-stimulated transcription of CD80 gene was elevated in cells treated with PPAR gamma-specific small interfering RNA (small interfering RNA, siRNA) compared to cells treated with CD40L alone (CD80/GAPDH mRNA = 0.11 +/- 0.04 vs. 0.05 +/- 0.02, respectively; p < 0.05), suggesting a regulatory role for PPAR gamma on the CD40/CD40L pathway. Altogether, our findings outline a novel mechanism through which PPAR gamma regulates the inflammatory signal initiated by activation of CD40, with important implications for the understanding of immunological mechanisms underlying SLE and the development of new treatment strategies. Lupus (2011) 20, 575-587.

Penile anthropometry in systemic lupus erythematosus patients

The aim of this study was to evaluate penile anthropometry in systemic lupus erythematosus (SLE) patients compared with healthy controls and the possible relevant pubertal, clinical, hormonal and treatment factors that could influence penile dimensions. Twenty-five consecutive SLE patients were assessed by urological examination, sexual function, testicular ultrasound, hormones, sperm analysis, genetic analysis, clinical features and treatment. The control group included 25 age-matched healthy males. SLE patients had a lower median penis length and circumference [8 (7.5-10) vs. 10 (8-13) cm, p = 0.0001; 8 (7-10) vs. 10 (7-11) cm, p = 0.001; respectively], lower median testicular volume by right and left Prader [15 (10-25) vs. 20 (12-25) ml, p = 0.003; 15 (10-25) vs. 20 (12-25) ml, p = 0.006; respectively], higher median of follicle-stimulating hormone [5.8 (2.1-25) vs. 3.3 (1.9-9) IU/l, p = 0.002] and lower morning total testosterone levels (28% vs. 0%, p = 0.009) compared with controls. In spite of that, erectile dysfunction was not observed in patients or controls. Analyses of lupus patients revealed that the median penis circumference was lower in patients with disease onset before first ejaculation compared with those with disease onset after first ejaculation [7.8 (7-10) vs. 9.0 (7.5-10) cm, p = 0.026]. No differences were observed in the median penile anthropometry regarding sexual dysfunction (p = 0.610), lower morning total testosterone levels (p = 0.662), oligo/azoospermia (p = 0.705), SLE Disease Activity Index >= 4 (p = 0.562), Systemic Lupus International Collaborating Clinics/ACR Damage Index >= 1 (p = 0.478), prednisone cumulative dose (p = 0.789) and intravenous cyclophosphamide therapy (p = 0.754). Klinefelters syndrome (46XY/47XXY) was diagnosed in one (4%) SLE patient with decreased penile size whereas Y-chromosomal microdeletions was absent in all of them. In conclusion, we have identified reduced penile dimensions in SLE patients with no deleterious effect in erectile function. Disease onset before first ejaculation seems to affect penis development in pre-pubertal lupus. Lupus (2011) 20, 512-518.

Fatal rhabdomyolysis in systemic lupus erythematosus

The authors describe herein the sixth lupus case that evolved with rhabdomyolysis. A 36-year-old woman with systemic lupus erythematosus was admitted to our hospital with malaise, myalgia, dysphagia, fever, preserved muscle strength, leukocytosis (15,600 cells), and increased creatine kinase of 1,358 IU/L that reached 75,000 IU/L in few days. She denied the use of myotoxic drugs and alcohol. Urine 1 showed false positive for hemoglobinuria (myoglobin) without erythrocytes in the sediment, confirming the diagnosis of rhabdomyolysis. Secondary causes were excluded. She was treated with hyperhydration and alkalinization of urine. Despite treatment, the patient developed pulmonary congestion and she died. The authors also review in this article rhabdomyolysis in patients with systemic lupus erythematosus.

Cutaneous vasculitis in systemic lupus erythematosus: association with anti-ribosomal P protein antibody and Raynaud phenomenon

Ninety-one consecutive systemic lupus erythematosus (SLE) patients (American College of Rheumatology criteria) with a history of cutaneous vasculitis were compared to 163 SLE controls without this clinical manifestation from July to December 2007 in order to determine the possible clinical and serological association of this manifestation. Data were obtained in an ongoing electronic database protocol and autoantibodies to anti-double-stranded DNA, anti-Sm, anti-RNP, anti-Ro/SS-A, anti-La/SS-B, and anticardiolipin and ribosomal P protein antibody (anti-P) were detected by standard techniques. Exclusion criteria were the presence of anti-phospholipid syndrome or antibodies, Sjogren syndrome, and a history of thrombosis. The mean age (38.5 +/- 11.5 vs. 37.8 +/- 11.6 years, p = 0.635), disease duration (12.5 +/- 7.8 vs. 11.8 +/- 7.9 years, p = 0.501), and frequency of white race (71.4% vs. 70.5%, p = 0.872) and female sex (96.8% vs. 93.7%, p = 0.272) were comparable in both groups. The vasculitis group had a higher frequency of malar rash (97.9% vs. 87.4%, p = 0.004), photosensitivity (91.4% vs. 81.6%, p = 0.030), and Raynaud phenomenon (RP; 27.7% vs. 7.5%, p < 0.001), whereas all other clinical manifestation including renal and central nervous system involvements were similar to the control group. Laboratorial data revealed that only anti-P (35.1% vs. 12.1%, p < 0.001) was more frequent in patients with vasculitis. In a multivariate logistic regression model, cutaneous vasculitis was associated to the presence of RP (OR = 3.70; 95% confidence interval [CI] = 1.73-8.00) and anti-P (OR = 3.42; 95% CI = 1.76-6.66). In summary, SLE cutaneous vasculitis characterizes a subgroup of patients with more RP and anti-P antibodies but not accompanied by a higher frequency of renal and central nervous system involvements.

Hormone profile in juvenile systemic lupus erythematosus with previous or current amenorrhea

To identify the underlying mechanism of amenorrhea in juvenile systemic lupus erythematosus (JSLE) patients, thirty-five (11.7%) JSLE patients with current or previous amenorrhea were consecutively selected among the 298 post-menarche patients followed in 12 Brazilian pediatric rheumatology centers. Pituitary gonadotrophins [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] and estradiol were evaluated in 32/35 patients, and prolactin and total testosterone in 29/35 patients. Patient`s medical records were carefully reviewed according to demographic, clinical and therapeutic findings. The mean duration of amenorrhea was 7.2 +/- A 3.6 months. Low FSH or LH was observed in 7/32 (22%) JSLE patients and normal FSH or LH in 25 (78%). Remarkably, low levels of FSH or LH were associated with higher frequency of current amenorrhea (57% vs. 0%, P = 0.001), higher median disease activity (SLEDAI) and damage (SLICC/ACR-DI) (18 vs. 4, P = 0.011; 2 vs. 0, P = 0.037, respectively) and higher median current dose of prednisone (60 vs. 10 mg/day, P = 0.0001) compared to normal FSH or LH JSLE patients. None of them had decreased ovarian reserve and premature ovarian failure. Six of 29 (21%) patients had high levels of prolactin, and none had current amenorrhea. No correlations were observed between levels of prolactin and SLEDAI, and levels of prolactin and SLICC/ACR-DI scores (Spearman`s coefficient). We have identified that amenorrhea in JSLE is associated with high dose of corticosteroids indicated for active disease due to hypothalamic-pituitary-ovary axis suppression.

Lymphocytic prolactin does not contribute to systemic lupus erythematosus hyperprolactinemia

Introduction Lymphocytic prolactin (PRL) gene expression is detected in the majority of the immune cells and it is not known if this source contributes to hyperprolactinemia in systemic lupus erythematosus (SLE). We have therefore evaluated lymphocytic PRL secretion and gene expression in SLE and healthy controls. Methods Thirty SLE patients (ACR criteria) and 10 controls were selected for the study. Serum levels of PRL and macroprolactin were detected by immunofluorometric assay and gel filtration chromatography, respectively. The lymphocytic biological activity was determined by Nb2 cells bioassays. Lymphocytic PRL gene expression was evaluated by RT-PCR assay. Results The median serum PRL levels of the 30 SLE patients was higher than the control group (9.65 (1.9-38.9) vs. 6.40 (2.4-10.3) ng/mL, p=0.03). A significant difference was detected between median serum PRL levels of active SLE, inactive SLE and controls (10.85 (5-38.9) vs. 7.65 (1.9-15.5) vs. 6.40 (2.4-10.3) ng/mL), p=0.01). The higher frequency of mild hyperprolactinemia was detected among active SLE in comparison with inactive SLE and controls (7(38.9%) vs. 1 (8.3%) vs. 0(0%)), with statistical significance (p=0.02). Nb2 cells assay revealed uniformly low levels of lymphocytic PRL in active, inactive and control groups without statistical significance among them (24.2 (8-63) vs. 27 (13.6-82) vs. 29.5 (8-72) ng/mL), p=0.84). Furthermore, median lymphocytic PRL gene expression evaluated by RT-PCR assay was comparable in both active and inactive SLE groups (p=0.12). Conclusion This is the first study to exclude a lymphocytic source of PRL, pointing out a pituitary etiology for hyperprolactinemia in SLE. However, other sources from the immune system cannot be ruled out.

Low bone mass in juvenile onset sclerosis systemic: the possible role for 25-hydroxyvitamin D insufficiency

Juvenile onset systemic sclerosis (JoSSc) is a rare disease, and there are no studies focusing in bone mineral density and biochemical bone parameters. Ten consecutive patients with JoSSc and 10 controls gender, age, menarche age, and physical activity matched were selected. Clinical data were obtained at the medical visit and chart review. Laboratorial analysis included autoantibodies, 25-hydroxyvitamin D (25OHD), intact parathyroid hormone, calcium, phosphorus, alkaline phosphatase and albumin sera levels. Bone mineral density was analyzed by dual-energy X-ray absorptiometry, and bone mineral apparent density (BMAD) was calculated. A lower BMAD in femoral neck (0.294 +/- A 0.060 vs. 0.395 +/- A 0.048 g/cm(3), P = 0.001) and total femur (0.134 +/- A 0.021 vs. 0.171 +/- A 0.022 g/cm(3), P = 0.002) was observed in JoSSc compared to controls. Likewise, a trend to lower BMAD in lumbar spine (0.117 +/- A 0.013 vs. 0.119 +/- A 0.012 g/cm(3), P = 0.06) was also found in these patients. Serum levels of 25OHD were significantly lower in JoSSc compared to controls (18.1 +/- A 6.4 vs. 25.1 +/- A 6.6 ng/mL, P = 0.04), and all patients had vitamin D insufficiency (< 20 ng/mL) compared to 40% of controls (P = 0.01). All other biochemical parameters were within normal range and alike in both groups. BMAD in femoral neck and total femur was correlated with 25OHD levels in JoSSc (r = 0.82, P = 0.004; r = 0.707, P = 0.02; respectively). We have identified a remarkable high prevalence of 25OHD insufficiency in JoSSc. Its correlation with hip BMAD suggests a causal effect and reinforces the need to incorporate this hormone evaluation in this disease management.

Effect of Severe Dietary Magnesium Deficiency on Systemic Bone Density and Removal Torque of Osseointegrated Implants

Purpose This study evaluated the effect of severe magnesium (Mg) dietary deficiency on systemic bone density and biomechanical resistance of bone tissue to the removal torque of osseointegrated implants Materials and Methods The sample consisted of 45 rats, each received a titanium implant in their tibial metaphysis After 60 days, the animals were divided into three groups (n = 15) according to their dietary Mg the control group received the recommended content of Mg, group Mg1 received a 75% reduction in dietary Mg content, and group Mg2 was fed a diet with a 90% reduction in Mg con tent Animals were sacrificed 150 days after implant placement Serum concentrations of Mg were measured and the effect of Mg deficiency on systemic bone density was evaluated by densitometry of the lumbar vertebrae and femur Biomechanical characteristics were measured by resistance of the bone tissue to removal of the implants Results Lower Mg serum concentrations were found for the Mg1 and Mg2 groups, however, densitometric analysis and torque evaluations showed a statistically significant difference only in the Mg2 group (P < 05) There was a statistically significant difference in removal torque between the Mg2 group and the control group Conclusions This study showed that a severe deficiency of Mg decreased the systemic bone density and removal torque of osseointegrated implants INT J ORAL MAXILLOFAC IMPLANTS 2010 25 1125-1130