A phase 1 study of the safety, reactogenicity, and immunogenicity of a Schistosoma mansoni vaccine with or without glucopyranosyl lipid A aqueous formulation (GLA-AF) in healthy adults from a non-endemic area.

BACKGROUND: Schistosomiasis caused by Schistosoma mansoni (Sm) is a chronic, debilitating and potentially deadly neglected tropical disease. The licensure of a vaccine to prevent schistosomiasis would represent a major breakthrough in public health. METHODS: The safety and immunogenicity of a candidate Sm vaccine were assessed in this phase I, double-blind, dose-escalation trial. Seventy-two healthy Sm-naïve 18-50 year olds were randomized to receive 3 doses ∼ 8 weeks apart of saline placebo, or 10 µg, 30 µg, or 100 µg of recombinant Sm-Tetraspanin-2 vaccine formulated on aluminum hydroxide adjuvant (Sm-TSP-2/Al) with or without 5 µg of glucopyranosyl lipid A aqueous formulation (GLA-AF). Clinical and serologic responses were assessed for 1 year after dose 3. RESULTS: Vaccines were safe and well-tolerated. The most common reactions were injection site tenderness and pain, and headache and fatigue. Tenderness and pain were more frequent in groups receiving vaccine with GLA-AF than placebo (p = 0.0036 and p = 0.0014, respectively). Injection site reactions among those given Sm-TSP-2/Al with GLA-AF lasted 1.22 and 1.33 days longer than those receiving Sm-TSP-2/Al without GLA-AF or placebo (p < 0.001 for both). Dose- and adjuvant-related increases in serum IgG against Sm-TSP-2 were observed. Peak IgG levels occurred 14 days after dose 3. Seroresponse frequencies were low among recipients of Sm-TSP-2/Al without GLA-AF, but higher among subjects receiving 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF. More seroresponses were observed among those given 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF compared to placebo (p = 0.023 and p < 0.001, respectively). Seroresponse frequencies were 0%, 30%, 50%, and 89%, respectively, among those given placebo, or 10 µg, 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF, suggesting a dose-response relationship for Sm-TSP-2/Al with GLA-AF (p = 0.0001). CONCLUSIONS: Sm-TSP-2/Al with or without GLA-AF was safe and well tolerated in a Sm-naïve population. A vaccine like the one under development may represent our best hope to eliminating this neglected tropical disease.

Young adults' immediate and delayed reactions to simulated marital conflicts: implications for intergenerational patterns of violence in intimate relationships.

This study investigated the thoughts and feelings that young adults from violent (VPA) and nonviolent (NPA) interparental-conflict backgrounds reported while listening to simulated marital conflicts and after a delay for reflection. While listening to conflicts, VPAs were more likely than NPAs to predict negative outcomes and to place blame. No between-groups differences regarding negative outcomes emerged after a delay. VPAs also reported perpetrating and experiencing more aggressive conflict in their dating relationships. Post hoc probes revealed that the negative-outcome-prediction and blaming variables played no significant mediating role in participants' intergenerational patterns of intimate-relationship aggression; however, methodological limitations likely compromised the statistical power for examining this mediational model. Results are discussed in light of research regarding intergenerational patterns of violence within families.

A laboratory study of root fillings in teeth obturated by lateral condensation of gutta-percha or Thermafil obturators.

The aim of this in vitro study was to assess the quality of root canal obturation and degree of apical dye penetration in teeth root-filled with either laterally condensed cold gutta-percha or Thermafil obturators. A total of 144 extracted teeth with single roots were included in the study. All canals were prepared with a standard technique using a sonic handpiece with copious irrigation. Radiographs taken of the teeth to show the maximum degree of canal curvature were then exposed and the angle, radius and position of curvature determined. This information about the canals, together with their working length and diameter at end-point was used to divide the teeth into two experimental and two control groups. A total of 71 teeth were filled with Thermafil obturators, 69 with lateral condensation while four teeth remained unfilled and acted as controls. Following obturation, the teeth were radiographed in two planes and the technical quality of fill assessed on a four-point scale. All access cavities were then sealed and the teeth immersed in dye for 48 h before being split longitudinally. Linear dye penetration via the apical foramen was then assessed. In both straight and curved canals obturation with Thermafil obturators was significantly quicker (P < 0.001) then lateral condensation. Apical extrusion of gutta-percha occurred significantly more often in straight canals obturated with lateral condensation (P < 0.005) but there was no difference in curved canals. There was little difference in the radiographic quality of fill in the apical halves of the root fillings but Thermafil obturators were significantly better in the coronal halves when viewed from the proximal.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of norfloxacin versus nalidixic acid in therapy of acute urinary tract infections.

Thirty-seven adult patients with acute urinary tract infections (UTI) were randomized to receive either a seven day (lower UTI) or a 14 day (upper UTI) course of norfloxacin 400 mg orally twice daily, or nalidixic acid 1 g orally four times per day. Mean age, underlying disease and infecting organisms were similar in the two groups. Nine patients in the norfloxacin group and seven in the nalidixic acid group had presumptive evidence of upper UTI. Overall, 12 patients had antibody-coated bacteria-positive infections. The infecting organisms were: Escherichia coli (27), coagulase-negative staphylococci (four), Citrobacter freundii (three), Klebsiella pneumoniae (three), and Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Enterobacter agglomerans, Streptococcus agalactiae, Enterococcus faecalis (one of each). All of the organisms were susceptible to norfloxacin, while 81% were susceptible to nalidixic acid. The effects on the periurethral and anal canal flora were similar in both groups. Five patients in each group experienced adverse clinical effects. The cure rates for norfloxacin and nalidixic acid were 79 and 83%, respectively. There were two failures, two relapses and four reinfections in the norfloxacin group. In the nalidixic acid group, there were two failures, one relapse and four reinfections. One of the failure patients in the nalidixic acid group developed resistance to the drug, and two of the four reinfections were due to organisms resistant to nalidixic acid. In this patient population it was concluded that nalidixic acid may be as effective as norfloxacin in the treatment of acute, symptomatic UTI.

The rapid emergence of high level gentamicin resistance in enterococci.

The proportion of enterococci isolated from blood and urine cultures that were highly resistant to gentamicin and streptomycin were determined. No blood or urine isolates highly resistant to gentamicin were seen in 1983, whereas by 1986-87 25% of blood and 17% of urine isolates were highly resistant. The rapid emergence of gentamicin resistance has serious implications for patients with life threatening enterococcal disease.

Double-blind, randomized comparison of 24 weeks of norfloxacin and 12 weeks of norfloxacin followed by 12 weeks of placebo in the therapy of complicated urinary tract infection.

We evaluated the benefits of prolonging norfloxacin therapy from 12 to 24 weeks for complicated urinary tract infection in a double-blind, randomized, placebo-controlled study. During the second 12 weeks, norfloxacin was superior to placebo (P less than 0.05) in suppressing bacteriuria. Adverse effects were common but mostly confined to the initial 12 weeks.

Risk of bacteremia with endoscopic sphincterotomy.

A prospective assessment of the risk of bacteremia with endoscopic sphincterotomy was made in 81 patients who underwent 95 procedures. Blood samples were taken for culture in all patients before and at 5 and 10 minutes after the last incision of the sphincter by the papillotome. An additional blood sample was obtained for culture within 30 seconds of the final incision in 32 of the 95 procedures. The rate of blood-culture positivity before the procedure was not significantly different from the post-incisional rate (1% compared with 3%, p greater than 0.05). No patient suffered from fever or chills during the 24 hours after sphincterotomy.

Prospective assessment of risk of bacteremia with colonoscopy and polypectomy.

A prospective assessment was made of the frequency of positive blood cultures in patients undergoing colonoscopy with or without polypectomy. A total of 270 patients underwent 280 colonoscopies, of these, there were 105 patients that had 111 polypectomies. Blood cultures were taken prior to and within 15 min following each procedure. Six of 280 (2.1%) preprocedural blood cultures were positive. Seven of 169 (4%) blood cultures were positive within 15 min of insertion of the colonoscope in the colonoscopy only group. Eight of 223 (3.6%) blood cultures were positive within 10 min of the polypectomy. There was no clinical evidence of sepsis during the 24 hr following these procedures. In order to determine appropriate postprocedural sampling intervals, we induced a Staphylococcus epidermidis bacteremia with a mean of 1.16 X 10(6) colony forming units/ml on 10 occasions in seven dogs. Within 30 min of inoculation, we were able to detect only one colony forming unit/ml. The rate of positive blood cultures during colonoscopy alone and following polypectomy during colonoscopy is comparable to other gastrointestinal endoscopy procedures. The most optimal time to collect blood cultures in order to detect transient bacteremia is as soon after the procedure as is feasibly possible.

Infectious complications of endoscopic injection sclerotherapy.

We prospectively assessed the infectious complications of esophageal injection sclerotherapy (EIS) in 38 patients who underwent 104 procedures. Blood cultures were taken prior to and five and ten minutes after injection of the sclerosing agent in all procedures in an attempt to determine the frequency of positive blood cultures. Surveillance cultures were obtained from each patient's pharynx and from the biopsy channel of the endoscope to identify potential sources of bacteremia. The rate of blood culture positivity before injection was not significantly different from that after injection (1.9% vs 4.3%). In only one procedure was the same organism isolated five and ten minutes after sclerotherapy. The isolate in both samples was a Corynebacterium species. Endoscope surveillance cultures were positive prior to 42 of 102 procedures, although none of those organisms subsequently were isolated in the blood cultures. Since the rate of positive blood cultures following EIS is no greater than that before the procedure, the use of prophylactic antibiotics is unnecessary.

Comparative trial of norfloxacin and trimethoprim-sulfamethoxazole in the treatment of women with localized, acute, symptomatic urinary tract infections and antimicrobial effect on periurethral and fecal microflora.

Forty-three women with acute, symptomatic urinary tract infections were randomized to receive either norfloxacin (400 mg) twice daily or trimethoprim-sulfamethoxazole (160-800 mg) twice daily for 10 days. Of the 43 patients, 7 (16%) had low-count bacteriuria and pyuria and were included in the evaluation. Escherichia coli was isolated in 72% of the infections, whereas coagulase-negative staphylococci were isolated in 14%. All isolates were susceptible to the assigned study drug. The MICs for 90% of the strains susceptible to norfloxacin and trimethoprim-sulfamethoxazole were less than or equal to 2 and less than or equal to 0.8-16 micrograms/ml, respectively. The cure rates for norfloxacin and trimethoprim-sulfamethoxazole were 95 and 90%, respectively. There were 17 patients with presumptive upper tract infections; only 1 of these relapsed after therapy. The effects on the periurethral flora were similar in both groups, but the infecting organism was eradicated from the fecal flora in 93% of the patients treated with norfloxacin and in 57% of the patients treated with trimethoprim-sulfamethoxazole. More early reinfections occurred in the trimethoprim-sulfamethoxazole group, with resistant organisms appearing in urine and in the periurethral and fecal flora in all cases. Three patients in each group experienced adverse clinical effects, but these were more severe in the trimethoprim-sulfamethoxazole group. No adverse hematological or biochemical changes were noted. From these results, we concluded that norfloxacin is at least as effective as trimethoprim-sulfamethoxazole in the therapy of acute, symptomatic urinary tract infections in women.

Infectious complications of endoscopic retrograde cholangiopancreatography. A prospective assessment.

A prospective assessment of the bacterial complications of endoscopic retrograde cholangiopancreatography (ERCP) was made in 97 unselected patients undergoing 101 endoscopies. Blood cultures were taken before and five and ten minutes after completion of the procedure. In an attempt to identify a potential source of infection, aspirates were taken from the pancreaticobiliary duct (PBD) after injection of contrast material. Blood cultures from all procedures were negative. In 14 patients PBD aspirates yielded Pseudomonas aeruginosa, pyocin type 22 and serotype O6, suggesting a common source for this organism. Isolation of this strain ceased after more rigorous cleansing and disinfection of the endoscope. The occurrence of bacteremia following ERCP is low, but there is a risk of transmission of potential nosocomial pathogens with this procedure.