Cyclosporin and tacrolimus: their use in a routine clinical setting for scleroderma.

BACKGROUND: Cyclosporin and tacrolimus are immunomodulatory drugs which act predominantly on T cells. Improvements in certain manifestations, particularly skin tightness, have been observed in a number of patients with scleroderma treated with these drugs. However, to date there have been no reports of their use in a routine clinical setting. METHODS: Patients attending clinical immunology clinics who had progressive systemic sclerosis and related syndromes and who had received cyclosporin and/or tacrolimus were identified. Details of their treatment, including drug dosage, duration of and response to treatment, side-effects and reasons for withdrawal, were recorded. RESULTS: Sixteen patients had been given cyclosporin and 13 of these had been treated for skin tightness. Half noticed significant softening of their skin whilst on treatment, and resolution was observed in all four of the patients treated for digital vasculitis. Side-effects were common and dose-limiting, and contributed to withdrawal in 12 out of 13 patients. Eight patients had been treated with tacrolimus; two of these had stopped the drug because of progression of their disease, one developed diarrhoea, prompting withdrawal, one stopped tacrolimus following improvement, and four remained on the drug. Side-effects had occurred in three patients. CONCLUSION: Improvements in skin occur in approximately half of all cases of scleroderma treated with either cyclosporin or tacrolimus, suggesting a beneficial effect. Side-effects, especially hypertension, are common with cyclosporin and often necessitate withdrawal. Adverse effects are also observed with tacrolimus, but in the small cohort so far treated only one patient had stopped the drug for this reason.

An audit of cyclosporin for systemic lupus erythematosus and related overlap syndromes: limitations of its use.

OBJECTIVE: To establish the usefulness of cyclosporin for systemic lupus erythematosus (SLE) in a routine clinical setting. METHODS: Patients who had received cyclosporin for SLE, mixed connective tissue disease, and other overlap syndromes were identified. Data relating to treatment with cyclosporin, including dosage, concurrent steroid use, response to treatment, side effects, and reasons for withdrawal, were extracted from medical notes. RESULTS: A total of 43 patients had been treated with cyclosporin between 1995 and 1998. Cyclosporin, average dose 4 mg/kg/d, was started in patients whose disease was active despite previous use of alternative second line agents. On every occasion when cyclosporin was used for thrombocytopenia the response was good, but when arthritis was the indication, the response was good in 14/26. The success rates for symptoms of arthralgia, myalgia, and fatigue were lower. Side effects occurred in 28/43 (65%) cases, and on 39/47 (83%) occasions cyclosporin was withdrawn owing to either side effects or failure to control disease activity, after a median duration of treatment of only four months. CONCLUSIONS: The response to cyclosporin is mixed and usually short lived.

Pregnancy outcome and family size in systemic lupus erythematosus: a case-control study.

OBJECTIVE: To establish pregnancy outcomes and family size in a geographically defined population of systemic lupus erythematosus (SLE) patients. METHODS: One hundred and thirty-eight SLE patients (all women satisfying at least four American Rheumatism Association criteria) and 276 age-matched female controls, from the Nottingham area, were interviewed by a single investigator. Demographic details and maternity histories were obtained, and the data collected were analysed statistically to calculate odds ratios (ORs) for risk of fetal loss (through miscarriage, stillbirth and abortion). Family size was also determined in White and non-White cases and controls. RESULTS: Women with SLE are at greater risk of spontaneous fetal loss than their healthy counterparts (OR = 2.21, 95% CI 1.46-3.35, P < 0.01) and they are more likely than controls to have a surgical abortion (OR 2.44, 95%, CI 1.22-4.87, P = 0.01). The excess risk of both of these outcomes exists both before and after diagnosis of SLE. The median number of children in White and non-White families of cases and controls is the same, i.e. two. White women with SLE, however, appear less likely than controls to have more than two children, whereas non-White lupus women tend to retain their propensity to have larger families, i.e. more than two children. CONCLUSIONS: We confirm that lupus women who have, or later develop, SLE are at greater risk of pregnancy loss by spontaneous or surgical means. We have also shown that race, and the inherent differences in social and cultural influences, appears to be an important determinant of ultimate family size; White women with SLE have fewer children than controls, whilst non-White lupus women tend to have larger families.

Prolonged central effects of quinpirole on cardiovascular regulation.

Central cardiovascular effects of the dopamine D2 receptor agonist quinpirole were studied in conscious rats. The i.v. injection of 0.3 mg/kg of quinpirole in spontaneously hypertensive rats (SHR) caused a rapid but short-lasting increase in blood pressure. Heart rate showed little change. Pretreatment with the centrally acting selective dopamine D2 receptor antagonist raclopride, but not the D1 antagonist SCH23390, completely prevented the rise in blood pressure. A second injection of quinpirole, 30 min after the first injection, induced little change in blood pressure, although at 4 or 24 hr after quinpirole treatment, we observed partial and complete recovery of the pressor response, respectively. This pattern of desensitization was similar to that seen after administration of the dopamine D2 receptor agonists N-propylnorapomorphine (0.3 mg/kg) or quinelorane (0.1 mg/kg), and was similar in spontaneously hypertensive rats, Wistar Kyoto and Sprague-Dawley rats. At 30 min after treatment with quinpirole, the hypotension induced by i.v. injection of clonidine (0.01 mg/kg) or of 8-hydroxy-dipropylaminotetralin (0.1 mg/kg) was markedly reduced when compared to that in saline-pretreated spontaneously hypertensive rats, suggesting a prolonged effect of quinpirole at the level of sympathetic regulation. The rapid fall in blood pressure caused by i.v. injection of the ganglion blocker pentolinium (10 mg/kg) was slightly, but significantly enhanced by treatment with quinpirole, which suggests an overall prolonged increase in resting sympathetic vasomotor tone. This would be difficult to reconcile with an inhibition of the action of sympatholytic drugs, unless it is hypothesized that the increase in sympathetic vasomotor tone was differential between different sympathetic beds or different neuronal populations in the brain. This may prohibit any additional pressor responses and, through a central feedback mechanism, may inhibit the action of sympatholytic drugs. No evidence was found for lasting changes in circulating levels of vasopressin, angiotensin or atrial natriuretic factor, nor were there changes in hematocrit. Cardiac sympathetic tone appeared to be enhanced, although vagal tone was normal and no major changes in baroreflex sensitivity were observed.

Molecular organization of sbcC, a gene that affects genetic recombination and the viability of DNA palindromes in Escherichia coli K-12.

The sbcC gene product of Escherichia coli interferes with the growth of a lambda red gam phage carrying a long palindrome in its DNA. This phenotype was used to identify recombinant plasmids harbouring the wild-type gene and to isolate sbcC mutant derivatives carrying Tn1000 insertions. Analysis of these plasmids located sbcC between proC and phoR at a slightly different position from that reported before (Lloyd, R.G. and Buckman, C. 1985, J. Bacteriol. 164, 836-844). Nucleotide sequencing revealed that the gene spans a DNA segment of 3.3 kb that encodes a poorly expressed protein of 118 kDa and which lies downstream of a gene of unknown function that encodes a polypeptide of 45 kDa. The amino acid sequence of SbcC contains a nucleotide binding fold similar to that in RecB and other recombination proteins.

Fenoprofen-induced immune hemolysis. Difficulties in diagnosis and complications in compatibility testing.

A 70-year-old man developed severe immune intravascular hemolysis and renal failure following ingestion of fenoprofen, a nonsteroidal, anti-inflammatory drug. The patient's red blood cells were sensitized with both IgG and C3d. The serum reacted with normal red blood cells in the presence and absence of the drug. Addition of albumin to the serum inhibited the reactivity with both neat and drug-treated serum. These atypical serologic findings for drug-related immune hemolytic anemia were explained by (1) the measurement of fenoprofen by high performance liquid chromatography (HPLC) in the neat serum; and (2) solid-phase adsorption studies showing that albumin can bind drug, leading to the disappearance of agglutination when albumin is added. This case demonstrates the utility of drug levels and adsorption techniques to confirm the diagnosis of drug-induced immune hemolytic anemia despite the anomalous serologic results which obscured the diagnosis and management of the patient.

Nucleotide sequence and LexA regulation of the Escherichia coli recN gene.

The nucleotide sequence of a 2224 bp region of the Escherichia coli chromosome that carries the LexA regulated recN gene has been determined. A region of 1701 nucleotides encoding a polypeptide of 567 amino acids with a predicted molecular weight of 63,599 was identified as the most probable sequence for the recN structural gene. The proposed initiation codon is preceded by a reasonable Shine-Dalgarno sequence and a promoter region containing two 16 bp sequences, separated by 6 bp, that match the consensus sequence (SOS box) for binding LexA protein. DNA fragments containing this putative promoter region are shown to bind LexA in vitro and to have LexA-regulated promoter activity in vivo. The amino acid sequence of RecN predicted from the DNA contains a region that is homologous to highly conserved sequences found in several DNA repair enzymes and other proteins that bind ATP. A sequence of 9 amino acids was found to be homologous to a region of the RecA protein of E. coli postulated to have a role in DNA/nucleotide binding.

Granulomatous encephalitis caused by Bipolaris hawaiiensis.

We describe a case of granulomatous encephalitis caused by Bipolaris (Drechslera) hawaiiensis in an immunocompetent patient. An 18-year-old man with a seven-month history of seizures and right leg weakness was found by computed tomographic scan to have a left frontoparietal enhancing lesion. Biopsy of the lesion revealed granulomatous inflammation and numerous septate hyphae. Culture of the biopsy specimen yielded a pure culture of B hawaiiensis in four days. Susceptibility studies revealed the organism to be sensitive to amphotericin B (minimal inhibitory concentration [MIC] equals 0.25 mg/L) and miconazole lactate (MIC equals 0.064 mg/L), but resistant to flucytosine (MIC greater than 100 mg/L). No synergy was demonstrated with amphotericin B and flucytosine in vitro. The patient was successfully treated with surgery and systemic and intrathecal amphotericin B therapy, and a negative culture was obtained from a repeated brain biopsy six weeks later.

Determination of norfloxacin and ciprofloxacin concentrations in serum and urine by high-pressure liquid chromatography.

A high-pressure liquid chromatographic method for the determination of norfloxacin or ciprofloxacin concentrations in body fluids was developed and compared with a standard bioassay. The high-pressure liquid chromatographic assay utilizes a reverse-phase C18 column, an internal standard, and fluorescence detection, with reproducibility studies yielding coefficients of variation ranging from 0.6 to 3.7% and 0.9 to 2.7% for norfloxacin and ciprofloxacin, respectively. Correlation coefficients with the bioassay were 0.966 for norfloxacin and 0.952 for ciprofloxacin.

Niemann-Pick disease--type C. Ocular histopathologic and electron microscopic studies.

The presence of lipid storage was demonstrated in type C Niemann-Pick disease by histopathologic and ultrastructural studies. Pleomorphic membranous inclusions, with variable proportions of light and dark granular material, were observed within the conjunctival fibrocytes, endothelial cells and pericytes, keratocytes, lens epithelium, retinal ganglion cells, retinal pigment epithelium, fibrocytes in the uveal tract, and optic nerve fibrous astrocytes. Only optic nerve and retinal ganglion cell involvement had clinical counterparts represented by optic nerve pallor and perimacular gray discoloration.

Farber's disease. Light and electron microscopic study of the eye.

A 35-month-old girl had Farber's disease (disseminated lipogranulomatosis) manifested clinically by macular cherry-red spots. The pathologic changes consisted of intracellular inclusions of varying morphologic features and density. The most frequently encountered inclusion was 1.2 micron wide and consisted of flattened stacks of osmophilic lamellae (2.1 to 2.3 nm thick, with 4.4-nm periodicity) oriented in parallel or oblique array ("zebra-body" configuration) and enclosed by a focally discontinuous unit membrane. Some of the inclusions contained curved tubular profiles resembling curvilinear tubular bodies. The retinal ganglion cells were grossly distended with inclusions and showed the greatest pathologic changes.

The recN locus of Escherichia coli K12: molecular analysis and identification of the gene product.

The recN gene which is necessary for inducible DNA repair and recombination in Escherichia coli has been cloned into the low copy plasmid vector pHSG415. Analysis of the recombinant plasmid, pSP100, revealed a 5.6 Kb HindIII insert of chromosomal DNA. Transposon inactivation of recN function and analysis of a recN::Mu(Ap lac) fusion located the coding region to a 1.4 Kb region within a 2.1 Kb BglII-AvaI DNA fragment transcribed in a clockwise direction with respect to the chromosome map. The gene product was identified in maxicells as a 60,000 dalton protein. Synthesis of this protein was increased in cells lacking LexA activity or in strains carrying recN cloned into the multicopy vector pBR322. Multiple copies of recN increase resistance to ionizing radiation in recN mutants but reduce the survival of a wild-type strain.