Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort.

We evaluated the roles of five single-nucleotide polymorphisms (SNPs) within PDCD1, and haplotypes defined by these SNPs, for the development of systemic lupus erythematosus (SLE) and specific sub-phenotypes (nephritis, antiphospholipid antibody positive, arthritis and double-stranded DNA positive) within a multiethnic US cohort of 1036 patients. Family based analyses were performed using 844 simplex families from four ethnic groups (Caucasian, Asian, Hispanic and African American). Subjects were genotyped for five 'tag' SNPs (selected from 15) to provide complete genetic information in all main ethnic groups. We employed transmission disequilibrium testing to assess risk for SLE by allele or haplotype, and multiple logistic regression analysis of SLE cases to examine associations with specific sub-phenotypes. In family based analyses, a haplotype containing the PD1.3A allele was significantly associated with SLE susceptibility among Caucasian families (P=0.01). Among Hispanic families, two novel SNPs were associated with SLE risk (P=0.005 and 0.01). In multivariate logistic regression analyses, five haplotypes were associated with specific sub-phenotypes among the different ethnic groups. These results suggest that PDCD1 genetic variation influences the risk and expression of SLE and that these associations vary according to ethnic background.

The effect of pharmacokinetics on the bactericidal activity of ciprofloxacin and sparfloxacin against Streptococcus pneumoniae and the emergence of resistance.

The pharmacokinetics of ciprofloxacin and sparfloxacin were simulated in vitro and the effects of pharmacodynamic parameters on bactericidal activity and the emergence of quinolone resistance were examined for Streptococcus pneumoniae. Simulated serum concentrations of ciprofloxacin 500 mg bd were more rapidly bactericidal than sparfloxacin 200 mg bd, despite lower values for the key pharmacodynamic parameters (AUC/MIC and C(max)/MIC). This was possibly related to the slower oral absorption of sparfloxacin, which delayed achievement of the MIC compared with ciprofloxacin. In addition, sparfloxacin was shown to have similar bactericidal activity to ciprofloxacin when tested at the same concentrations, despite its four-fold better potency in MIC terms. The emergence of resistance following exposure to ciprofloxacin appeared to be dependent on the C(max)/MIC ratio and the AUC above the MIC, but not the AUC/MIC ratio. Resistance (at least four-fold increase in MIC) developed when the C(max)/MIC ratio was less than four or the AUC above the MIC was less than 10, and the resulting cultures regrew fully. In contrast, pneumococci with a two- to four-fold increase in sparfloxacin MIC were selected in the presence of serum concentrations of sparfloxacin despite a C(max)/MIC ratio higher than 12, but these isolates remained clinically susceptible by breakpoint MIC and their growth was inhibited by repeated dosage of sparfloxacin. Nevertheless, the selection of pneumococci with reduced susceptibility, and the possibility of further mutation to highly resistant strains supports the use of quinolones that rapidly eradicate pneumococci at conventional doses and achieve concentrations, in both serum and tissues, which exceed at least 4 x MIC.

Recurrent atrial electrode displacement complicating a single lead VDD pacing system.

We describe an unusual complication of single-lead VDD pacing: recurrent advancement of the atrial bipole into the right ventricle. As a consequence, the patient experienced symptomatic pacemaker-mediated tachycardia and underwent two revision operations to achieve adequate fixation of the lead.

Bacteriological efficacies of three macrolides compared with those of amoxicillin-clavulanate against Streptococcus pneumoniae and Haemophilus influenzae.

Comparative antibacterial efficacies of erythromycin, clarithromycin, and azithromycin were examined against Streptococcus pneumoniae and Haemophilus influenzae, with amoxicillin-clavulanate used as the active control. In vitro, the macrolides at twice their MICs and at concentrations achieved in humans were bacteriostatic or reduced the numbers of viable S. pneumoniae slowly, whereas amoxicillin-clavulanate showed a rapid antibacterial effect. Against H. influenzae, erythromycin, clarithromycin, and clarithromycin plus 14-hydroxy clarithromycin at twice their MICs produced a slow reduction in bacterial numbers, whereas azithromycin was bactericidal. Azithromycin at the concentrations achieved in the serum of humans was bacteriostatic, whereas erythromycin and clarithromycin were ineffective. In experimental respiratory tract infections in rats, clarithromycin (equivalent to 250 mg twice daily [b.i.d.]) and amoxicillin-clavulanate (equivalent to 500 plus 125 mg b.i.d., respectively) were highly effective against S. pneumoniae, but azithromycin (equivalent to 500 and 250 mg once daily) was significantly less effective (P < 0.01). Against H. influenzae, clarithromycin treatment (equivalent to 250 or 500 mg b.i.d.) was similar to no treatment and was significantly less effective than amoxicillin-clavulanate treatment (P < 0.01). Azithromycin demonstrated significant in vivo activity (P < 0.05) but was significantly less effective than amoxicillin-clavulanate (P < 0.05). Overall, amoxicillin-clavulanate was effective in vitro and in vivo. Clarithromycin and erythromycin were ineffective in vitro and in vivo against H. influenzae, and azithromycin (at concentrations achieved in humans) showed unreliable activity against both pathogens. These results may have clinical implications for the utility of macrolides in the empiric therapy of respiratory tract infections.

In vitro activities of oral beta-lactams at concentrations achieved in humans against penicillin-susceptible and -resistant pneumococci and potential to select resistance.

The beta-lactam susceptibilities of 65 strains of Streptococcus pneumoniae for which penicillin MICs covered a broad range were assessed. The order of potency was amoxicillin (AMX) = amoxicillin-clavulanate (AMC) > penicillin G > cefpodoxime (CPO) > cefuroxime (CXM) > cefprozil > cefaclor > loracarbef > cefixime. No decrease in susceptibility was seen following repeated subculture of two penicillin-susceptible strains of S. pneumoniae in AMX, AMC, cefaclor, or loracarbef, whereas repeated exposure to CPO and CXM resulted in 4- to 32-fold decreases in susceptibility for both strains. When one of these strains was exposed to concentrations of CPO, CXM, AMX, and AMC achieved in the serum of humans following the administration of an oral dose, all agents were rapidly bactericidal, with no decrease in susceptibility up to 72 h. This was consistent with antibiotic concentrations exceeding the MICs for 100% of the dosing interval. For a penicillin-resistant strain, MICs were exceeded for 29% of the 12-h dosing interval for 500 mg of AMX, 42% of the interval for AMC with 875 mg of AMX and 125 mg of clavulanate (875/125 mg of AMC) 21% of the interval for 500 mg of CXM, and 0% of the interval for 200 mg of CPO. Consequently, only 875/125 mg of AMC produced a sustained bactericidal effect. A four- to eightfold reduction in susceptibility to CPO and CXM and cross-resistance with cefotaxime, but not penicillin or AMC, were selected following exposure to simulated serum CPO and CXM concentrations. In addition, AMX and AMC were the only agents which consistently produced a >99% reduction in bacterial numbers in time-kill studies using concentrations of antibiotic achieved in middle ear fluid for all three strains of penicillin-resistant S. pneumoniae tested.

Gastrin and colorectal cancer: a prospective study.

BACKGROUND & AIMS: Gastrin is a putative promoter of colorectal carcinomas. The aim of this study was to evaluate the temporal relationship between gastrinemia and development of colorectal malignancy. METHODS: We conducted a nested case-control study among 128,992 subscribers to a health maintenance program who had participated in a multiphasic health checkup between 1964 and 1969. Serum had been frozen since the checkup and the cohort followed up for cancer. Of 1881 incident colorectal carcinoma cases, 250 were randomly selected; 1 control without cancer was matched to each case by age, sex, education, and date of serum collection. Stored sera were tested for Helicobacter pylori immunoglobulin G and for gastrin and glycine-extended gastrin. RESULTS: Verified cases included 166 colon cancers, 58 rectal cancers, and 9 with cancer in both locations. A mean of 15.3 years had elapsed between serum collection and diagnosis of cancer. Median gastrin levels were similar in cases and controls (41.7 vs. 40.7 pg/mL). However, a gastrin level above normal was associated with increased risk for colorectal malignancy (odds ratio, 3.9; 95% confidence interval, 1.5-9.8). If this association is causal, 8.6% of colorectal cancers could be attributed to high serum gastrin level. CONCLUSIONS: Hypergastrinemia is associated with an increased risk of colorectal carcinoma.

Inappropriate rate change in minute ventilation rate responsive pacemakers due to interference by cardiac monitors.

Observations of inappropriate rate increase in five patients with minute ventilation rate responsive implanted pacemakers (Telectronics Meta) are reported. Pacing rate increases were observed immediately upon connection of the resting patients to two brands of widely used cardiac monitors, and one commonly used echocardiograph. In some circumstances, the rate increase remained until monitor disconnection; in others the rate increase was transient, lasting and 20 seconds. A hardware thoracic resistance variation simulator was constructed and connected to one of the pacemakers to test sensitivity to rate modifying interference from external sources. This demonstrated that the sensitivity to interference is dependent upon the frequency of the interfering signal and is highest in the range 10-60 kHz, that peak currents as low as 10 microA can cause maximum rate increase, and that the signals injected into patients by several cardiac monitors, for purposes of lead-off detection or respiratory monitoring, fall into the frequency range at which the pacemaker is most susceptible to interference.

Postantibiotic and post-beta-lactamase inhibitor effects of amoxicillin plus clavulanate.

The postantibiotic effect (PAE) of amoxicillin-clavulanate was studied for strains of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, and Escherichia coli. A PAE of approximately 2 h was seen for beta-lactamase-positive and -negative strains of S. aureus following 2 h of exposure to twice the MIC and did not increase at 16 times the MIC. The PAE observed with H. influenzae was clearly related to the growth rate of the organism. A PAE of 0.8 h was found for amoxicillin (four times the MIC) against a beta-lactamase-negative strain of H. influenzae (generation time, 26.3 min) and a PAE of 1.74 h was found for amoxicillin-clavulanate (twice the MIC) against a beta-lactamase-positive strain (generation time, 32.2 min). When the beta-lactamase-positive strain was growing more slowly (generation time, 120 min), the PAE of amoxicillin-clavulanate increased to > 3.32 h. The PAE of amoxicillin-clavulanate at 2/1 micrograms/ml on a beta-lactamase-producing strain of M. catarrhalis was > 2.9 h, and, as expected, the PAEs of twice the MIC on K. pneumoniae and E. coli were generally short (< 1 h). The post-beta-lactamase inhibitor effect (PLIE), determined after removal of only clavulanate, was also examined for beta-lactamase-positive strains. This was more prolonged (approximately 3 to 4 h) than the corresponding PAE for S. aureus, H. influenzae, and M. catarrhalis. The PLIE was related to the amount of beta-lactamase produced and required the presence of amoxicillin in the initial exposure period. These data may have implications for reducing the dosage of amoxicillin-clavulanate.

Epidemiology of gastric non-Hodgkin's lymphoma patients: parallels with Helicobacter pylori.

BACKGROUND: The incidence of gastric non-Hodgkin's lymphoma (NHL) is increasing in the United States. However, little is known about the etiology of the disease. Some studies have shown an association between gastric NHL and Helicobacter pylori. No study has specifically delineated demographic features that distinguish gastric NHL patients from nongastric NHL patients. MATERIALS AND METHODS: To obtain information about the differences between gastric and nongastric NHL patients, we conducted a hospital chart review study. We examined charts of all 25 cases of primary gastric NHL, as well as charts of 75 randomly selected nongastric NHL patients as controls. All patients were seen in the Division of Oncology at Stanford University Medical Center from 1972 to 1991. Demographic information was tabulated, and differences between the cases and controls were noted. The identified risk factors were determined by both univariate and logistic regression analyses. RESULTS: There was no difference between gastric NHL cases and nongastric controls with respect to age, gender, race, and family history of any cancer. However, in logistical regression, persons with gastric NHL were more likely than those with other forms of NHL to be born outside the United States (odds ratio = 12.8; 95% confidence interval = 2.9-56.0) and also to have a family history of stomach cancer (odds ratio = 18.4; 95% confidence interval 2.1-160.1). CONCLUSIONS: Gastric NHL is more likely than NHL at other sites to occur in persons with a family history of gastric cancer or in those born in developing countries. This epidemiological pattern supports the identified role of H. pylori in the development of gastric lymphoma.

Interaction between RNA-dependent RNA polymerase of alfalfa mosaic virus and its template: oxidation of vicinal hydroxyl groups blocks in vitro RNA synthesis.

In the life cycle of a (+)-strand RNA plant virus the processes of template RNA recognition and initiation of the synthesis of a complementary strand by the viral RNA-dependent RNA polymerase (RdRp) are crucial early steps. Using a template-dependent in vitro RNA synthesizing system of alfalfa mosaic virus (AIMV) we were able to study the effect of small chemical modifications of the 3' end of the template RNAs on product formation. After oxidation of the 3'-terminal nucleoside of the template no products could be detected. Presumably, RNA synthesis was blocked at the stage of initiation, since the promoter of the RdRp is internal (A. C. Van der Kuyl et al., Virology 176, 346-354, 1990). Blocking was probably due to an irreversible binding of the enzyme to the 3' end of the modified RNA. Using this system it was shown that in template competition experiments the RdRp of AIMV displays a high specificity for its cognate template, either before or after the oxidation of the 3'-terminal nucleoside. From this it was concluded that periodate modification of the 3'-terminal nucleoside has little or no effect on template recognition. Furthermore, we showed that the viral coat protein, which forms a part of the viral polymerase (R. Quadt et al., Virology 182, 309-315, 1991), was not the main target involved in the inhibition of RNA synthesis.

Idiopathic right ventricular tachycardia: electrophysiology and response to catheter ablation.

BACKGROUND: Ventricular tachycardia (VT) originating in the right ventricle may be seen in the absence of structural heart disease. Although this is thought to be associated with a benign course, it may cause intolerable symptoms and be difficult to control with antiarrhythmic drugs. AIMS: To assess the value of radiofrequency ablation of right ventricular tachycardia and to characterise the clinical and electrophysiologic features predictive of successful ablation. METHODS: Nine patients (aged 20-49 years) with clinical VT underwent cardiac mapping which localised the site of origin of VT in the right ventricle. At least three separate areas of VT origin were identified in these patients. Ablation of VT was defined as suppression of VT at the time of hospital discharge. RESULTS: Five patients had successful ablation of the tachycardia focus with long term suppression of the arrhythmia. Patients with successful ablation were characterised by inability to induce VT with extrastimuli, a distinct VT morphology with a rS pattern in lead 1, right axis deviation, facilitation of VT with isoprenaline and site of origin in the lateral outflow tract. During VT, an earlier site of presystolic activation was found in successful patients compared with unsuccessful ablations. Right ventricular tachycardia in patients without structural heart disease is a heterogeneous disorder with varied clinical and electrophysiologic features. Successful ablation of VT may be predicted by consideration of these variables.

Transesophageal echocardiography before and during direct current cardioversion of atrial fibrillation: evidence for "atrial stunning" as a mechanism of thromboembolic complications.

OBJECTIVES: The purpose of this study was to evaluate the usefulness of transesophageal echocardiography before electrical cardioversion in patients with atrial fibrillation and to determine the mechanism of thromboembolism after cardioversion. BACKGROUND: Thromboembolic complications after electrical cardioversion of atrial fibrillation have been attributed to the dislodgment of preexistent left atrial thrombus during the resumption of atrial contraction. Transesophageal echocardiography has been proposed as a method of screening patients for left atrial thrombus before cardioversion. METHODS: Seventy transesophageal echocardiographic studies were performed in 66 patients, predominantly with nonvalvular atrial fibrillation, before direct current cardioversion. In addition, transesophageal echocardiography was performed during the cardioversion procedure in 15 patients and immediately after in 1 patient. RESULTS: Left atrial thrombus was detected in one patient (1.4%), and cardioversion was cancelled. Thromboembolic complications occurred in 4 patients, none of whom had evidence of left atrial thrombus before cardioversion. Within 10 s of successful cardioversion, left atrial spontaneous echo contrast appeared in five patients, increased in one patient and was unchanged in nine patients. Patients with new or increased spontaneous echo contrast had more impaired atrial contraction and slower initial heart rates after cardioversion than those without. Left ventricular contraction was also impaired transiently by cardioversion. CONCLUSIONS: Transesophageal echocardiographic detection of left atrial thrombus before direct current cardioversion is important but infrequent in patients with predominantly nonvalvular atrial fibrillation. The occurrence of thromboembolic complications in the absence of demonstrable left atrial thrombus and the new development of spontaneous echo contrast in association with the transient atrial dysfunction ("stunning") caused by cardioversion suggest that cardioversion may promote new thrombus formation, in which case all patients should receive full anticoagulant therapy at the time of cardioversion.

Prognostic implications of loss of late potentials following acute myocardial infarction.

The prognosis of patients following myocardial infarction is adversely affected by the finding of late potentials at the time of hospital discharge. Loss of late potentials has been previously reported during serial testing during the first year after infarction, but it is not known whether such patients remain at risk of arrhythmic events. This study prospectively followed 243 patients after myocardial infarction. Late potentials were observed in 92 patients (group I) at the time of hospital discharge. Of these patients, 23 no longer had late potentials at 6-week follow-up and 8 had had an arrhythmic event (sudden death or ventricular tachycardia). In patients with loss of late potentials, overall QRS duration had decreased from 109 +/- 11 msec at discharge to 104 +/- 11 msec (P < 0.01), terminal QRS voltage rose from 15 +/- 4 microV to 31 +/- 9 microV (P = 0.001), and late potential duration fell from 42 +/- 6 msec to 28 +/- 6 msec (P = 0.001) at the 6-week study. Predictors of loss of late potentials were: initial duration of the QRS duration (P < 0.001) and terminal voltage (P < 0.005); non-Q wave infarction (P < 0.001); and being a male (P < 0.05). After the 6-week assessment, 11 additional arrhythmic events occurred during median follow-up of 31 months. The risk of arrhythmic events was similar in patients with loss of late potentials and those who retained late potentials in group I (9% vs 11%, P = NS) but significantly greater than patients with no late potentials at discharge (group II, 2%).(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmogenic right ventricular dysplasia.

A 23-year-old man presented with recurrent exercise-induced ventricular tachycardia (VT), complicated by systemic embolisation. Catecholamine--sensitive VT was reproduced on exercise testing and programmed electrical stimulation, displaying features suggestive of enhanced automaticity as well as re-entry. Both 2D-echocardiography and gated heart pool scan showed localised dyskinetic bulging in the right ventricle. A diagnosis of arrhythmogenic right ventricular dysplasia was made. This condition should be excluded in all young patients with otherwise unexplained ventricular arrhythmias.