Longitudinal associations of active renal disease with irreversible organ damage accrual in systemic lupus erythematosus.

OBJECTIVE: To examine longitudinal associations of active lupus nephritis with organ damage accrual in patients with systemic lupus erythematosus (SLE). METHODS: This study was performed using data from a large multinational prospective cohort. Active lupus nephritis at any visit was defined by the presence of urinary casts, proteinuria, haematuria or pyuria, as indicated by the cut-offs in the SLE Disease Activity Index (SLEDAI)-2K, collected at each visit. Organ damage accrual was defined as a change of SLICC-ACR Damage Index (SDI) score >0 units between baseline and final annual visits. Renal damage accrual was defined if there was new damage recorded in renal SDI domains (estimated glomerular filtration rate <50%/proteinuria >3.5 g per 24 h/end-stage kidney disease). Time-dependent hazard regression analyses were used to examine the associations between active lupus nephritis and damage accrual. RESULTS: Patients (N = 1735) were studied during 12,717 visits for a median (inter-quartile range) follow-up period of 795 (532, 1087) days. Forty per cent of patients had evidence of active lupus nephritis at least once during the study period, and active lupus nephritis was observed in 3030 (24%) visits. Forty-eight per cent of patients had organ damage at baseline and 14% accrued organ damage. Patients with active lupus nephritis were 52% more likely to accrue any organ damage compared with those without active lupus nephritis (adjusted hazard ratio = 1.52 (95% confidence interval (CI): 1.16, 1.97), p < 0.02). Active lupus nephritis was strongly associated with damage accrual in renal but not in non-renal organ domains (hazard ratios = 13.0 (95% CI: 6.58, 25.5) p < 0.001 and 0.96 (95% CI: 0.69, 1.32) p = 0.8, respectively). There was no effect of ethnicity on renal damage accrual, but Asian ethnicity was significantly associated with reduced non-renal damage accrual. CONCLUSION: Active lupus nephritis measured using the SLEDAI-2K domain cut-offs is associated with renal, but not non-renal, damage accrual in SLE.

The cellular response to herpes simplex virus type 1 (HSV-1) during latency and reactivation.

In order to learn more about the cellular response to viral gene activity during latency and reactivation of herpes simplex virus type 1 (HSV-1), the authors have employed microarray analysis. On an array of about 1200 cellular genes, approximately 56 genes were found to be differentially regulated in infected trigeminal ganglia of mice, compared to uninfected mice, during latency and reactivation. Of these genes, 10 were examined more closely using quantitative real-time polymerase chain reaction (PCR) to confirm the microarray results. Genes involved in interferon and other signaling pathways appeared to predominate in response to a latent or reactivating HSV infection. Interestingly, some genes found to be differentially regulated in latently infected ganglia are neuronal-specific genes (pro-opiomelanocortinin; zinc finger proteins of the cerebellum 1 and 2). During reactivation, the involvement of several cell signaling molecules that may be important for the initiation of an HSV infection was observed, including various receptors and molecules involved in cell-cell spread.

During lytic infection herpes simplex virus type 1 is associated with histones bearing modifications that correlate with active transcription.

Herpes simplex virus type 1 (HSV-1) is a large (150-kb) double-stranded DNA virus that forms latent infections in neuronal cells of the human peripheral nervous system. Previous work determined that the HSV-1 genome is found in an ordered nucleosomal structure during latent infection. However, during lytic infection, it was unclear whether viral DNA was in a chromatin state. We examined HSV-1 during lytic infection using micrococcal nuclease digestion and chromatin immunoprecipitation. The HSV-1 genome is at least partially nucleosomal, although apparently not in a regular repeating structure. Analysis of histones associated with HSV-1, within both the promoter and the transcribed regions, revealed covalent amino tail modifications similar to those associated with active host mammalian genes. Certain of the modifications were detected in the temporal order expected of the immediate-early, early, and late gene classes. These data suggest that productive infection may be accompanied by acquisition of a permissive chromatin state.

Azithromycin: an assessment of its pharmacokinetics and therapeutic potential in CAPD.

BACKGROUND: Azithromycin is an azalide antibiotic with a similar antibacterial spectrum to erythromycin but with greater gram-negative activity. Azithromycin displays a favorable pharmacokinetic profile, with improved absorption and higher sustained tissue concentrations compared with erythromycin. This results in a prolonged elimination half-life, suggesting a potential for treating continuous ambulatory peritoneal dialysis (CAPD) peritonitis. OBJECTIVE: This study aimed to define the potential role of azithromycin in treating CAPD peritonitis. DESIGN: The pharmacokinetics and peritoneal dialysis (PD) clearance of azithromycin were studied following a single 500-mg oral dose of azithromycin. Blood and dialysate samples were taken over a 10-day period and assayed using high-pressure liquid chromatography. SETTING: The study took place within the Renal Unit at Southend Hospital NHS Trust, a district general hospital in the United Kingdom. PATIENTS: Eight patients with oliguric end-stage renal failure without peritonitis maintained on CAPD (3 x 2 L/day). RESULTS: Peak plasma concentrations occurred at 2-3 hours with 0.35-1.35 microg/mL (mean 0.75). The mean elimination half-life was 84.55 hrs, and plasma clearance was 21.93 L/hour. This compares with values of greater than 40 hours and 40.8 L/hour reported in healthy volunteers. After 8 hours, the mean dialysate concentration was 0.07 microg/mL; PD clearance was 0.06 L/hr. CONCLUSION: Azithromycin is not substantially removed by CAPD in the absence of peritonitis and cannot be recommended for widespread use in this setting at present. However, the successful use of azithromycin in CAPD peritonitis, due possibly to an intracellular drug transport mechanism, has been reported. Future research should address this possibility.

A survey of CAPD peritonitis management and outcomes in North and South Thames NHS regions (U.K.): support for the ISPD guidelines. International Society for Peritoneal Dialysis.

OBJECTIVE: This survey examined the current management of continuous ambulatory peritoneal dialysis (CAPD) peritonitis and the effectiveness of the various antibiotic protocols in use. DESIGN: The information required was elicited via a postal questionnaire. SETTING: The questionnaire was posted to each renal dialysis unit offering CAPD throughout the North and South Thames National Health Service regions. PATIENTS: All patients using CAPD at each responding unit were eligible for inclusion. MAIN OUTCOME MEASURES: Each unit provided details of their CAPD peritonitis episodes for 1997. Each unit's empirical treatment regimen for CAPD peritonitis was sought in addition to response rates. Also requested were numbers for peritonitis episodes, recurrences, and negative cultures, plus the peritonitis rate per patient-month. RESULTS: Thirteen units returned the questionnaire (87% of the survey population). Nine of the 13 units were using vancomycin regimens, with the remainder using cephalosporin regimens. The results were compared to the audit standards of the British Renal Association. Seventy percent of units reached the 80% mark for response rate; similar results were achieved with both the vancomycin and cephalosporin regimens. Ninety-two percent achieved the suggested peritonitis rate of 1 episode every 18 patient-months; 30% achieved the culture-negative rate of 10%. The average recurrence rate was 19%. CONCLUSION: The units contacted achieved most of the standards suggested by the British Renal Association; however, wide variations did exist. Recent guidelines have suggested avoiding vancomycin-based regimens in order to reduce the incidence of vancomycin resistance. The suggested regimen of a cephalosporin with an aminoglycoside seems to represent a suitable alternative.

Diabetic amyotrophy without pain. A puzzling clinical picture.

A patient with weight loss and weakness presents a diagnostic challenge. Drs Moeser and Kent describe an unusual case of diabetic amyotrophy that required extensive workup to arrive at the diagnosis and rule out more serious disease. Symptoms were dramatic, and recovery was spontaneous following conservative treatment.

Reactions of the intervening sequence of the Tetrahymena ribosomal ribonucleic acid precursor: pH dependence of cyclization and site-specific hydrolysis.

During self-splicing of the Tetrahymena rRNA precursor, the intervening sequence (IVS) is excised as a unique linear molecule and subsequently cyclized. Cyclization involves formation of a phosphodiester bond between the 3' end and nucleotide 16 of the linear RNA, with release of an oligonucleotide containing the first 15 nucleotides. We find that the rate of cyclization is independent of pH in the range 4.7-9.0. A minor site of cyclization at nucleotide 20 is characterized. Cyclization to this site becomes more prominent at higher pHs, although under all conditions examined it is minor compared to cyclization at nucleotide 16. The circular IVS RNAs are unstable, undergoing hydrolysis at the phosphodiester bond that was formed during cyclization. We find that the rate of site-specific hydrolysis is first order with respect to hydroxide ion concentration, with a rate constant 10(3)-10(4)-fold greater than that of hydrolysis of strained cyclic phosphate esters. On the basis of these results, we propose that circular IVS RNA hydrolysis involves direct attack of OH- on the phosphate at the ligation junction, that particular phosphate being made particularly reactive by the folding of the RNA molecule. Cyclization, on the other hand, appears to occur by direct attack of the 3'-terminal hydroxyl group of the linear IVS RNA without prior deprotonation.

Sequence requirements for self-splicing of the Tetrahymena thermophila pre-ribosomal RNA.

The sequence requirements for splicing of the Tetrahymena pre-rRNA have been examined by altering the rRNA gene to produce versions that contain insertions and deletions within the intervening sequence (IVS). The altered genes were transcribed and the RNA tested for self-splicing in vitro. A number of insertions (8-54 nucleotides) at three locations had no effect on self-splicing activity. Two of these insertions, located at a site 5 nucleotides preceding the 3'-end of the IVS, did not alter the choice of the 3' splice site. Thus the 3' splice site is not chosen by its distance from a fixed point within the IVS. Analysis of deletions constructed at two sites revealed two structures, a hairpin loop and a stem-loop, that are entirely dispensable for IVS excision in vitro. Three other regions were found to be necessary. The regions that are important for self-splicing are not restricted to the conserved sequence elements that define this class of intervening sequences. The requirement for structures within the IVS for pre-rRNA splicing is in sharp contrast to the very limited role of IVS structure in nuclear pre-mRNA splicing.

A labile phosphodiester bond at the ligation junction in a circular intervening sequence RNA.

The excised intervening sequence of the Tetrahymena ribosomal RNA precursor mediates its own covalent cyclization in the absence of any protein. The circular molecule undergoes slow reopening at a single phosphodiester bond, the one that was formed during cyclization. The resulting linear molecule has 5'-phosphate and 3'-hydroxyl termini; these are unusual products for RNA hydrolysis but are typical of the other reactions mediated by this molecule. The reopened circle retains cleavage-ligation activity, as evidenced by its ability to undergo another round of cyclization and reopening. The finding that an RNA molecule can be folded so that a specific phosphate can be strained or activated helps to explain how the activation energy is lowered for RNA self-splicing. The proposed mechanisms may be relevant to several other RNA cleavage reactions that are RNA-mediated.

Endemic goiter in Vietnam.

Endemic goiter involves about 15% of the population of Vietnam. To define the role of various factors which contribute to endemic goiter in Vietnam, we surveyed 935 people in Vancon, a lowland commune with goiter appearing only in the past decade, and 619 people in Dich Giao, a highland commune with endemic goiter treated erratically with iodized salt. In Dich Giao, cassava, a goitrogenic food, constitutes half of the dietary caloric intake. The prevalence of goiter was 45% in Vancon and 28% in Dich Giao. Laboratory studies were carried out in a subgroup of 63 subjects in Vancon, 52 subjects in Dich Giao, and a control group of 46 women in Hanoi. The mean serum TSH levels were 1.4 +/- 0.1 (+/- SE) microU/ml in Hanoi, 3.6 +/- 0.5 microU/ml in Vancon (P less than 0.001), and 2.4 +/- 0.2 microU/ml in Dich Giao (P less than 0.05). The mean serum T4 concentrations were similar in the three groups, but the mean free T4 concentration was low in Vancon. Serum T3 levels and the T3 to T4 ratios were significantly elevated in the goitrous regions. The mean serum thyroglobulin (Tg) concentrations were 27 +/- 3 ng/ml in Hanoi, 101 +/- 20 ng/ml in Vancon (P less than 0.01), and 44 +/- 5 ng/ml in Dich Giao (P less than 0.01). The 4-h thyroid uptake was higher in Vancon than in Hanoi. The urinary iodine concentration was low in both goitrous regions, and urinary thiocyanate was increased in Dich Giao, reflecting the ingestion of cassava. For all regions combined, there was a direct correlation between serum TSH and T3 and between serum TSH and Tg. In Vancon, where iodine deficiency was more severe, there was an inverse correlation between thyroid uptake and the urinary iodine concentration; thyroid uptake correlated directly with serum T3, the T3 to T4 ratio, and serum Tg. In Dich Giao, there was no correlation between urinary thiocyanate and thyroid uptake or urinary iodine levels. The data show that low iodine intake is a major factor in the causation of goiter in Vancon, where iodine deficiency had not been suspected. The ingestion of cassava in Dich Giao did not cause a major change in thyroid hormone economy even though iodine intake was marginally low; the data suggest that the goitrogenic effect of cassava is easily overcome by supplementary iodine, even when it is ingested irregularly.

Immunosuppression by sex steroid hormones. The effect upon PHA- and PPD-stimulated lymphocytes.

Progesterone, estradiol, testosterone, cortisol, and 11-desoxycortisol (compound S) were added to cultures of human lymphocytes stimulated with phytohaemagglutinin (PHA) and purified protein derivative (PPD). The immunosuppressive effect of cortisol was verified and the three sex-steroid hormones also were found to inhibit lymphocyte transformation although at concentrations higher than for cortisol. Compound S, a steroid of low biological potency, also had immunosuppressive activity. At concentrations (0-01-1-0 microng/ml), progesterone, oestrogen, testosterone, and Compound S augmented the transformation response to PPD but not to PHA. Marked variation from individual to individual in the suppressive effects of all the steroids were noted. The clinical implications of immunosuppression by the sex steroid hormones are discussed.

Myocardial infarction and carbohydrate metabolism relating to diabetes mellitus.

Fifteen non-obese males with acute myocardial infarction and no diabetic history were evaluated for diabetes. During infarction, results of oral glucose tolerance tests were "diabetic" or "probably diabetic" in 10 of the 15 patients (67 percent). The plasma immuno-reactive insulin response in 12 patients (80 percent) was of a pattern observed in patients with maturity-onset diabetes. Six months after infarction, follow-up glucose tolerance tests in 12 surviving patients were diabetic or probably diabetic in three cases (25 percent). In seven of twelve patients (58 percent) had delay in the peaking of the plasma insulin response to an oral glucose tolerance test, a phenomenon that is observed in patients with maturity-onset diabetes. Glucose tolerance tests were abnormal in one of fourteen control subjects (7 percent). There was a delayed plasma insulin response to an oral glucose test in two of fourteen controls (14 percent). Patients with myocardial infarction have an increased incidence of diabetes mellitus.