Rituximab induction without maintenance for granulomatosis with polyangiitis and dialysis - Case report and literature review.

ANCA-associated vasculitis (AAV) may lead to irreversible organ damage, particularly end-stage renal disease (ESRD) requiring dialysis. The chances of renal recovery diminish with prolonged dialysis. We describe a case of a 32-year-old woman admitted for pulmonary infiltrates and acute renal failure. Autoimmune workup revealed an elevated titer of proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA). The diagnosis of granulomatosis with polyangiitis (GPA) was confirmed by renal biopsy. The patient received induction therapy with IV rituximab (375 mg/m2 per week for 4 weeks) along with systemic high-dose IV corticosteroids and one pulse of IV cyclophosphamide (1000 mg). Rapid deterioration of her kidney function led to pulmonary edema requiring intensive care (ICU) hospitalization. Dialysis and plasmapheresis were initiated. Significant clinical improvement ensued, but the patient remained dialysis dependent. No immunosuppressive maintenance therapy other than prednisone was given. Chronic dialysis was discontinued successfully after eight months. At a follow-up of 30 months since her hospitalization, the patient is in complete remission without relapses. We suggest that rituximab induction without maintenance therapy for GPA ESRD may be adequate.

An unusual infection outbreak in rats held in a human hospital research laboratory.

Most animal hazards in laboratories are widely recognized. These, together with zoonoses and other possible insults, are subject to the establishment of guidelines for the operation and maintenance of such facilities. Most of the infectious diseases described among laboratory animals are related to the inadequate implementation of preventive and quality control policies. These included surgical, respiratory and intestinal tract infections, and typically spread between animals. This report is about an outbreak of nosocomial bacterial infection in rats held in the research laboratory of a human hospital. Symptoms of general infection were runny nose and sneezing, excessive lachrymation, dyspnea, loss of appetite, limited activity and disheveled fur, which appeared in two rats initially, and spread to another 60. A common characteristic physical finding observed later was a lump under the skin, with subsequent ulceration. Mortality was 70%. Blood cultures were sterile. Accurate diagnosis was possible only after examination of tissue sampled from the diseased and dead rats. Histology showed an excessive proliferative and inflammatory reaction. Bacteriology analysis revealed the presence of three types of hospital-borne bacteria: enterococcus, coagulase-negative staphylococci and Acinetobacter radioresistens, with common sensitivity to ciprofloxacin and ceftazidime. Empiric antibiotic therapy was switched to a bacteriology-based regimen. Complete recovery was achieved among the diseased rats that survived the previous antibiotic therapy. This is the first written description of a nosocomial infection of laboratory animals caused by bacteria borne in a human hospital. Medical staff-to-animal transmission is suggested. A high index of suspicion and prompt diagnostic evaluation are essential for successful management, and preventive guidelines concerning such events need to be established.

Effect of sevelamer hydrochloride exposure on carotid intima media thickness in hemodialysis patients.

BACKGROUND: Elevated phosphorus (P) and calcium (Ca)-P product (Ca × P) are associated with vascular calcification and cardiovascular disease (CVD) morbidity and CVD and all-cause mortality. OBJECTIVES: This study examined the effect of sevelamer hydrochloride exposure (regardless of calcium carbonate exposure) on carotid and femoral intima media thickness (IMT), reliable surrogate measures of prospective intimal thickening, in end-stage renal disease patients on maintenance hemodialysis. METHODS: The present cross-sectional study is nested in the Sevelamer hydrochloride and ultrasound-measured femoral and carotid intima media thickness progression in end-stage renal disease (SUMMER) clinical trial. Carotid and femoral arteries were visualized in B-mode ultrasonography. Log-transformed IMT was compared by sevelamer hydrochloride exposure and modeled using multiple linear regression. RESULTS: Forty-five subjects were exposed to sevelamer hydrochloride and 130 were not. Exposed subjects had significantly lower carotid IMT, an association which persisted in the multiple linear regression model even after controlling for potentially confounding variables including serum Ca, history of CVD and body weight. Exposed subjects had lower low-density lipoprotein cholesterol levels and significantly higher parathyroid hormone, but no differences in P, Ca and Ca × P. CONCLUSIONS: Sevelamer hydrochloride was associated with lower carotid IMT. This association may be mediated through reduction in Ca load, low-density lipoprotein cholesterol lowering or some other pleiotropic effect.

Effects of the radiofrequency interference with modified titanium surgical clips on liver parenchyma--an in vivo experiment.

AIM: This study sets out to test the biocompatibility of titanium clips in liver, in the presence of radiofrequency. Biocompatibility is assessed at various distances from the RF electrode and different points in time. METHOD: It is an experimental study conducted on pigs and makes use of histological changes that occur at the liver-titanium interface in presence of RF to test hypotheses. The titanium clips were modified in high vacuum (10 -5 atm) by heating them at 1000 degrees C and 1150 degrees C. Titanium clips were placed in liver at 0.5, 1.5 and 2.5 cm from RF probe. At 7, 14 and 28 days the inflammation, necrosis and fibrosis were assessed. RESULTS: The histological alterations decrease with the distance of implantation of titanium clips. The inflammation and necrosis nearby the titanium clips decrease in time, but the fibrosis does not increased, as expected. The modified titanium at 1000 degrees C clips cause less necrosis than commercial titanium clips. The moderator role of clip type between distance and cell alteration is empirically supported only for fibrosis and necrosis. The moderator role between time and cell alteration is supported only for inflammation. CONCLUSIONS: Experimental data suggests there are no preferred surgical clips in all situations. The biocompatibility of the titanium clips depends on the distance from the RF probe. The commercial ones prove less damaging if they are placed close to the RF probe (less than 1 cm) and those that were treated at 1150 C have a better bio-compatibility if placed more than 1 cm from RF probe.

[Accessory renal allotransplantation with internal or external urinary drainage. An experimental model in pig]. / Allotransplantarea renala accesorie cu drenaj urinar intern sau extern. Model experimental la porc.

This study describes an experimental model of accessory renal allotransplantation in the big laboratory animal (pig). A total of 24 common-breed pigs were used. All allografts were transplanted in an accessory manner and revascularized at the level of the infrarenal abdominal aorta and inferior vena cava. The urinary drainage was performed either through a nexternal uretheroneostomy at the ipsilateral lumbar region (Group A--n=8) or by internal uretheroneocystostomy (Group B--n=8). All transplants were monitored for 8 days postoperatively using translumbar ultrasound-guided biopsies at 1, 4, 7 days. A total of 16 transplants were performed. 1 ectopic donor kidney was found and transplanted in the same fashion. Mean operative time was 125 minutes, immediate postoperative survival was 100% and at 72 hours, 87.5%. The onset of acute rejection was at day 4, by massive lymphocyte infiltration and was directly correlated with the abrupt decrease of the allograft diuresis in Group A, at day 3. At day 7, the rejection was complete. Both methods of urinary drainage are functional and can be employed. This experimental model is a useful tool for training of the transplant surgeons or for transplantation research. The surgical technique for accessory renal allotransplantation in pig is easy to learn and offers the possibility for allograft monitoring until complete rejection without influencing the receptor health condition.

Assessement by laser Doppler of the peripheral tumour perfusion after radiofrequency ablation for colorectal liver mestasis--experimental study.

Colorectal cancer became one of the most frequent malignant conditions of the past two decades. Non-resecable liver metastases might be destroyed in situ by radiofrequency although the local recurrence is still very important. Laser-Doppler flowmetry has proved to be a simple technique for monitoring the microcirculation, hereby the tissue perfusion at the edge of the post radiofrequency necrosis. The aim of the study was to evaluate microcirculation using lasser-Doppler for hepatic tissue and peripheral tumour perfusion after radiofrequency and the influence of local temperature increasing at 42 degrees C on tissular perfusion. Colorectal adenocarcinoma (CC531s) was used for liver tumour inoculationin on 15 Wag/Rij rats. Twenty-one days after inoculation, perfusion in hepatic tissue, on the tumour before and after radiofrequency treatment was mesured. When hepatic tissue was heated at 42 degrees C there was an increase in tissular perfusion, on the other part, heating the tumoural tissue do not increase perfusion. After radiofrequency in the periphery of necrosis the perfusion was still present, despite a clear drop towards initial level. Assessing the local microcirculation and tissue temperature during RF ablation by Laser-Doppler might be useful not only for RF efficiency evaluation but also as an indication for associating adjuvant local chemotherapy.

Human anti-60 kD heat shock protein autoantibodies are characterized by basic features of natural autoantibodies.

Anti-human Hsp60 autoantibodies--known risk factor of atherosclerosis--were investigated in a mouse model and in samples of healthy subjects: polyreactivity, presence in cord blood samples of healthy newborns and life-long stability were tested. In IgM hybridoma panel from mouse spleens, polyreactivity of anti-Hsp60 autoantibodies was studied. In healthy pregnant women, umbilical vein and maternal blood samples were collected after childbirth, anti-Hsp-60 and -65 IgM and IgG levels were measured. Life-long stability of anti-Hsp-60 levels was studied on healthy patients during 5 years. ELISA was used in all studies. Polyreactivity of IgM clones of newborn mice and lifelong stability of these autoantibodies in healthy adults were established. IgM anti-Hsp60 autoantibodies in cord blood of healthy human infants were present, however, there was no correlation between maternal and cord blood IgM anti-Hsp60 concentrations. It is proposed that presence of anti-Hsp60 autoantibodies--as part of the natural autoantibody repertoire--may be an inherited trait. Level of anti-Hsp60 autoantibodies may be an independent, innate risk factor of atherosclerosis for the adulthood.

A Y-chromosomal comparison of the Madjars (Kazakhstan) and the Magyars (Hungary).

The Madjars are a previously unstudied population from Kazakhstan who practice a form of local exogamy in which wives are brought in from neighboring tribes, but husbands are not, so the paternal lineages remain genetically isolated within the population. Their name bears a striking resemblance to the Magyars who have inhabited Hungary for over a millennium, but whose previous history is poorly understood. We have now carried out a genetic analysis of the population structure and relationships of the Madjars, and in particular have sought to test whether or not they show a genetic link with the Magyars. We concentrated on paternal lineages because of their isolation within the Madjars and sampled males representing all extant male lineages unrelated for more than eight generations (n = 45) in the Torgay area of Kazakhstan. The Madjars show evidence of extensive genetic drift, with 24/45 carrying the same 12-STR haplotype within haplogroup G. Genetic distances based on haplogroup frequencies were used to compare the Madjars with 37 other populations and showed that they were closest to the Hungarian population rather than their geographical neighbors. Although this finding could result from chance, it is striking and suggests that there could have been genetic contact between the ancestors of the Madjars and Magyars, and thus that modern Hungarians may trace their ancestry to Central Asia, instead of the Eastern Uralic region as previously thought.

Association between early onset and organ manifestations of systemic lupus erythematosus (SLE) and a down-regulating promoter polymorphism in the MBL2 gene.

The serum concentration of mannose-binding lectin (MBL) is genetically determined by a series of allelic polymorphisms in the MBL2 gene. Since several polymorphisms of the MBL2 gene have been suggested to be risk locus for systemic lupus erythematosus (SLE), we investigated MBL2 polymorphisms in 315 SLE patients from Hungary and 182 geographically matched healthy controls. Within the group of patients, we found that homozygotes for an MBL2 down-regulating promoter polymorphism at position -221 (YA to XA) (rs7096206) were significantly (p=0.017) younger at diagnosis than the other patients. The frequency of juvenile-onset SLE (

Reflex gain of muscle spindle pathways during fatigue.

There are conflicting observations of the effects of fatigue on the sensitivity of large diameter Ia afferents. Our goal was to characterize any fatigue-related changes in the spinal reflex pathways during fatigue. Manipulation of the Ia afferent response by vibration and tendon tap, in which the motor neuron pool is modulated by both short- and long-loop activation from muscle spindles, were elicited before and after a fatigue task. The fatigue task consisted of intermittent submaximal and maximal voluntary contractions (MVCs). Percent voluntary activation fell from 98.75% MVC to 80.92% MVC following the fatigue task as measured by the twitch interpolation technique. Voluntary contractions of the same force profile as the force produced by 30 s of vibration were produced by having participants (n = 10) follow the trajectory on a computer monitor, before and after the fatigue task. Recruitment thresholds (RTs) of voluntarily activated units showed no change during fatigue; however, units activated via the reflex pathway were recruited approximately 30% sooner during fatigue (P < 0.05). The ratio of the electrical-to-mechanical response of the tendon tap increased significantly with fatigue. Our findings of decreased RTs in response to vibration and increased EMG activity during the tendon tap following the fatigue task indicate that Ia afferent input to the motoneuron pool was increased. The decrease in MVC force indicates that during this time the descending drive was compromised. These results provide evidence that the gain of the gamma loop is increased during fatigue, indicating possible peripheral neural compensation to the motor neuron pool in order to preserve force output.

Pregnancy in membranous glomerulonephritis--course, treatment and outcome.

BACKGROUND: The effect and outcome of pregnancy in women with preexisting glomerulonephritis is a controversial issue. CASE: We report the clinical course and treatment of a 23-year-old pregnant woman with biopsy-proven membranous glomerulonephritis. When she conceived, the patient had been in stable remission for 1 year. In the 14th week of pregnancy, the patient developed uncontrolled hypertension and nephrotic syndrome. Daily 1 g methylprednisolone intravenous pulses were administered for 3 days, followed by a 4-week course of oral prednisone, 50 mg/day. Clinical improvement and normalization of arterial blood pressure were achieved. Oral prednisone 60 mg was administered on alternate days for another 4 weeks following 3 days of pulse therapy. At the end of treatment (26th gestational week), we observed a decrease of proteinuria (from 10.6-4.8 g/24 h) and rise in serum albumin (from 2.1-2.9 g/100 ml). At this time, blood pressure was 130/85. In the 34th week, a normal healthy male newborn was delivered by cesarean section. One year later she felt well, her blood pressure was 140/90, serum albumin was 3.4 g/100 ml, urine protein was 1.65 g/24 h and renal function was normal. The patient's child was healthy and well developed. CONCLUSION: Judicious use of a specific therapy to the underlying renal disease during pregnancy, together with a continuous supervision, can improve outcomes of these particular high-risk conditions.

Pamidronate-induced nephrotoxic tubular necrosis--a case report.

Few cases of pamidronate (bisphosphonate class of drugs) nephrotoxicity in humans have been previously reported in the literature. In 7 patients, the pamidronate-related nephrotoxicity was attributed to focal collapsing glomerulosclerosis [Markowitz et al. 2001], and in 1 patient was related to tubulo-interstitial inflammatory nephritis [Van Doom et al. 2001]. We report herein on a 65-year-old Caucasian female patient who presented with acute chronic renal failure due to pamidronate-induced toxic proximal tubular necrosis without immunologic or inflammatory tubulo-interstitial involvement. The acute pattern of renal failure resolved following cessation of pamidronate administration in this patient for osteoporosis; the patient also had a monoclonal gammopathy of unspecific origin (MGUS).

High level of anticholesterol antibodies (ACHA) in HIV patients. Normalization of serum ACHA concentration after introduction of HAART.

Anticholesterol antibodies (ACHA) are natural antibodies against the 3beta-OH group of cholesterol. Since lipid disorders are common in HIV infection and HAART may further enhance dislipidaemia, we determined by using an ELISA method serum ACHA concentrations in HIV patients and healthy HIV-seronegative controls. ACHA levels were almost 4 times higher in the sera of 46 patients than in 110 controls. No difference in the specificity of ACHA was found between HIV-seropositive and HIV-seronegative sera. Binding of ACHA to cholesterol-coated plates from a HIV-seropositive serum was dose-dependently inhibited by preincubation with HIV-1(BA-L) preparation. Serum concentration of ACHA was significantly higher in the patients with low serum cholesterol levels than in those with normal cholesterol levels. HAART induced a marked drop of ACHA concentration. We found a significant negative correlation between the length of HAART and the ACHA levels. By contrast, HAART did not significantly influence total IgG concentration and titers of antibodies against 60 kD heat shock protein. Our findings indicate that high levels of ACHA in HIV-infection may contribute to the development of hypocholesterolaemia frequently observed in this disease.

Serum malondialdehyde and prevalent cardiovascular disease in hemodialysis.

BACKGROUND: Oxidative stress has been proposed as a mechanism by which the accelerated rate of cardiovascular disease (CVD) observed in maintenance hemodialysis (HD) patients may be explained. This study examined the effects of HD and CVD on serum malondialdehyde (MDA) levels as a marker of oxidative stress in HD patients with and without prevalent CVD. Serum MDA levels and CVD prevalence in HD were modeled. METHODS: Serum MDA was determined using spectrophotometry in HD patients (N = 76, 53 men and 23 women, mean age 63.8 years) immediately prior to and at the conclusion of one midweek HD treatment. Traditional CVD risk factors, including serum lipids, lipoproteins, apolipoproteins, and fibrinogen, were also measured, as were serum chemistry and dialysis adequacy. RESULTS: Mean serum MDA levels were significantly elevated in HD patients with prevalent CVD compared with those without, whereas serum lipoprotein and plasma fibrinogen levels did not differ between the two groups. Patients in the highest compared with the lowest tertile of postdialysis MDA were nearly four times as likely to have prevalent CVD, and serum MDA was the single strongest predictor of prevalent CVD in this patient population. CONCLUSIONS: These findings indicate the presence of oxidative stress in HD patients, and are consistent with the theory of oxidative stress as a factor in accelerated CVD in this population.

Comparison of hemostatic factors and serum malondialdehyde as predictive factors for cardiovascular disease in hemodialysis patients.

Hemodialysis (HD) patients have accelerated cardiovascular morbidity and mortality rates compared with the general population. Identifying the factors that predict major coronary events in this population can direct the focus on prevention. This cross-sectional study compares known and suspected cardiovascular risk factors in HD patients with and without prevalent cardiovascular disease (CVD). In 76 HD patients (prevalent CVD, 44 of 76 patients), serum lipid, lipoprotein, apolipoprotein (Apo), plasma fibrinogen, tissue plasminogen activator (TPA), plasminogen activator inhibitor (PAI-1), and factor VII levels were measured using standard kits. Serum malondialdehyde (MDA; a marker of oxidative stress) was measured using spectrophotometry. Predictor variables were compared using analysis of variance and chi-squared tests, as appropriate. CVD prevalence was modeled using multiple logistic regression analysis, and odds ratios (OR) were calculated. Serum lipid, lipoprotein, Apo, plasma TPA, PAI-1, and factor VII values did not differ significantly from laboratory norms or discriminate for prevalent CVD in HD patients. Plasma fibrinogen levels were significantly elevated in HD patients compared with laboratory norms (369.4 +/- 130.02 v 276.7 +/- 77.7 mg/dL; P < 0.0001) but were not significantly different in HD patients with and without prevalent CVD. Serum MDA levels, both before and after the midweek HD treatment, were significantly elevated in all HD patients compared with laboratory norms (pretreatment, 2.6 +/- 0.8 nmol/mL; posttreatment, 2.1 +/- 0.3 v 0.91 +/- 0.09 nmol/mL; P < 0.01) and were significantly elevated in HD patients with prevalent CVD versus those without (pretreatment, 2.8 +/- 0.6 v 2.4 +/- 0.4 nmol/mL; P < 0.01; posttreatment, 2.3 +/- 0.4 v 1.94 +/- 0.2 nmol/mL; P < 0.01). Only serum MDA levels, both before and after the midweek treatment, contributed to the explanation of variation in CVD prevalence. OR for CVD in the highest versus lowest tertile of pretreatment MDA level was 2.71 (95% confidence interval [CI], 1.42 to 5.19). ORs for CVD in the highest versus lowest tertile of posttreatment MDA level was 3.65 (95% CI, 1.6 to 8.32).

IL-10 expression in thyroid glands: protective or harmful role against thyroid autoimmunity?

IL-10 is a cytokine which not only suppresses cellular immunity but also stimulates the humoral response. In certain animal models of autoimmunity, IL-10 exerts a protective effect against autodestruction. This study was to ascertain whether there could be a role for IL-10 in human autoimmune thyroid disease. Total RNA was extracted from snap-frozen thyroid blocks from surgical specimens. Five 'normal', five multinodular, six Graves and two Hashimoto thyroids (one euthyroid and one hypothyroid) were studied. Approximately 7 microg of total RNA from each gland were reverse transcribed with oligo-dT primers. Pre-plateau semiquantitative polymerase chain reaction (PCR) was performed with specific IL-10 primers. PCR products were run on a 1-5% agarose gel, blotted onto a N-hybond nylon membrane, hybridized with a specific internal probe labelled with gamma-32P-ATP and autoradiographed. Statistical analysis of densitometric values showed significantly higher IL-10 levels in the autoimmune than in the non-autoimmune glands. In situ hybridization and immunohistochemistry showed that the IL-10 message was located within the infiltrating lymphomononuclear cells. Histological analysis revealed that the autoimmune thyroids with the highest IL-10 levels were characterized by relevant degrees of B and T cell infiltration and also exhibited the greatest percentage of spontaneous HLA class II expression on thyrocytes. IL-10 and neutralizing anti-IL-10 antibodies were not able to regulate in vitro spontaneous or interferon-gamma (IFN-gamma)/phytohaemagglutinin (PHA)-induced HLA class II on thyrocytes. We conclude that in active autoimmune thyroiditis, in addition to the well documented production of Th1 cytokines, Th2-related lymphokines can be detected simultaneously. It can be envisaged that in this condition the role of IL-10 might be directed to the stimulation of B cell proliferation and antibody production rather than to the suppression of proinflammatory cytokine release.

Patterns of dietary intake and serum lipids interact with proteinuria as risk factors for progression of chronic renal failure.

UNLABELLED: This prospective study assessed the interactions between patterns of nutrient intake and serum lipids with other risk factors for progression of chronic renal failure. The study cohort consisted of 52 individuals with documented chronic renal failure, 18 women and 34 men, with a mean age of 65 +/- 11 years at the time of recruitment. The dependent variable was the rate of progression of chronic renal failure, which was determined by the slope of the curve generated from five or more values of the reciprocal of serum creatinine (SCr-1) and divided by time (in months of follow-up) for each patient, and recorded in dung/month. The independent variables included dietary factors (phosphorus, protein); serum lipids (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides); proteinuria; serum phosphorus; serum albumin; serum glucose; and blood pressure. Serum creatinine was drawn in a fasting state and determined using the picric acid technique on five or more occasions for each patient. The mean monthly rate of decline in dL/mg/month was calculated for each patient. The cohort was followed for 1.5 years. Descriptive statistics were determined for all variables. Analysis of principal components was used to generate variables representing patterns of nutrient intake and serum lipids. The outcome variable was modeled using stepwise linear regression which included principal components representing dietary and serum lipid patterns. The Student's t test and the F test were used for hypothesis testing. All tests were significant at p < 0.05. RESULTS AND CONCLUSIONS: Multicolinearity prevented the inclusion of more than one individual dietary or serum lipid variable into the multiple linear regression model of rate of decline in kidney function. Principal components representing patterns of dietary intake and serum lipids, contributed to the prediction of rate of decline in renal function together with proteinuria.

Carnitine palmitoyltransferase deficiency: an underdiagnosed condition?

Two apparently healthy adults were admitted because of acute muscle cramps, severe weakness, and red urine excretion. Patient No. 1 developed the symptoms following intense exercise and patient No. 2 during a febrile infection. Both of them experienced such episodes in the past, but these were medically misinterpreted. Their present manifestations were accompanied by renal failure which subsided gradually and was found to be a result of rhabdomyolsis and myoglobinuria. Further investigations yielded a deficiency of carnitine palmitoyltransferase as a background to the acute muscular destruction. Examination of a sister of patient No. 2 who had a similar past history revealed the same metabolic disorder. Carnitine palmitoyltransferase deficiency, as a cause of nontraumatic rhabdomyolysis, is a distinct entity in the pathogenesis of acute renal failure. Our experience (3 patients within 2 years) makes us presume that this condition is not as rare as hitherto reported and should rather be considered in cases of 'nonhematuric' red urine and acute renal failure.

In situ localization of HLA class I mRNA in human testis.

We have used a 0.35-kilobase (kb) antisense RNA probe complementary to the monomorphic regions of both classical and nonclassical HLA class I sequences to detect histocompatibility-class-I-antigen-specific mRNA in human testicular tissue. The message has been clearly detected in the interstitium while less intensive staining was revealed in the peribasal compartment of the seminiferous epithelium.