Stepwise safety trial of a killed Leishmania vaccine in Iran

We retrospectively analyzed 36 patients requiring temporary abdominal wall closure on admission to a level I trauma center from 1988 to 1992. There were 10 deaths (28%) in the study population. Of the 26 survivors, 8 patients (31%) had primary fascial closure at initial hospitalization, whereas 18 patients (69%) required split-thickness skin grafting to visceral granulation tissue. Of these 18 patients, 13 have had ventral herniorrhaphy at subsequent admission. Eight of these patients had primary fascial closure, 4 required primary fascial approximation with prosthetic onlay reinforcement, and 1 required multiple operations including prosthetic reconstruction and eventual complex tissue transfer. Complications occurred in 3 patients (14%) and included two wound seromas, which were drained nonoperatively, and a wound infection necessitating removal of prosthetic material and subsequent reconstruction with complex tissue transfer. Follow-up reveals no recurrent hernia at 24 months. Abdominal wall reconstruction after temporary closure can be done safely and promptly, with good functional and esthetic results.     

Immunogenicity and protective role of three formulations of oral cholera vaccine

Three formulations of oral cholera vaccine were compared with respect to their immunogenicity and protective ability in a rat ileal loop model. Eight-week-old Wistar rats were divided into five groups. The first group received orally vaccine A consisting of liposome-associated V. cholera lipopolysaccharide, fimbriae and procholeragenoid, whereas the rats of groups 2 and 3 received orally vaccines B and C consisting of heatkilled fimbriated and non-fimbriated whole cell V. cholerae, respectively. Rats of groups 4 and 5 were controls that received orally liposomes alone and normal saline solution, respectively. It was found that vaccine A elicited stronger immune responses to all three V. cholerae antigens. The antibody responses were detected in both serum and intestinal lavage samples. Vaccine B elicited only modest serum and intestinal responses to V. cholerae fimbriae (anti-F). No detectable immune response was found in rats of group 3 immunized with vaccine C. Rats immunized with vaccines A and B had a similar order of magnitude of numbers of vibrios adhered to their intestinal mucosa. These numbers were less than those associated with the intestinal tissues of control rats of groups 4 and 5 by about two orders of magnitude. Although without any detectable immune response, rats of group 3 that were immunized with vaccine C showed some reduction in numbers of vibrios associated with their intestinal mucosa. The numbers of vibrios recovered from the intestinal segments of rats of all treatment groups were in the order group 1 = 2 < 4 = 5. Electron micrography also revealed patches of vibrio colonization on the mucosa of rats of groups 3, 4 and 5. These features were not found in the groups vaccinated with vaccines A and B. The inhibition of vibrio colonization afforded by the vaccines was biotype- and serotype-non-specific. The results suggest that the heat-killed whole cell fimbriated V. cholerae may be an alternative vaccine preparation to the liposome-associated refined antigen vaccine at a lower cost.     

Field trial with a new type of influenza subunit vaccine (author's transl)

In a field trial a new influenza subunit vaccine was tested in parallel with a vaccine prepared from the whole virus. The subunit vaccine essentially contained only the proteins of the viral envelope, haemagglutinin and neuraminidase, which had been selectively solubilized by treatment with cetyl trimethylammonium bromide. Both vaccines contained 700 IU of strain A/Port Chalmers/73 in 0.5 ml. They were given to volunteers by the subcutaneous route with and without the addition of Al (OH)3 as adjuvant. Blood samples were taken on days 0, 28 and 90. Development of antibodies was assayed in the haemagglutination-inhibition (HI) and neuraminidase-inhibition (NI) test. All vaccines exhibited a very good immunogenic effect as judged from the number of volunteers with at least a four-fold rise in antibodies in the HI-test and those reaching titres that are considered to be sufficiently high for protection against disease. The best results were obtained with the aqueous subunit vaccine. All four vaccines also stimulated the formation of neuraminidase-inhibiting antibodies. The vaccines were well tolerated by the volunteers. The incidence of minor local reactions such as redness, swelling and pain varied according to the vaccine used, as shown on statistical evaluation. The aqueous subunit vaccine clearly proved to be superior in this respect.     

Further molecular characterization and stability of the live oral attenuated cholera vaccine strain CVD103-HgR

Vibrio cholerae CVD103-HgR, the first live attenuated vaccine licensed for human use produced by recombinant DNA technology, was genetically compared to its parent strains 569B and CVD103. The genetic stability for both lyophilized vaccine in final container form and for viable organisms shed from vaccinees was determined. Results obtained lead us to conclude: (i) the genetic composition of the examined genes in CVD103-HgR is identical to that of the parent strains except for the alterations induced; (ii) the level of mercury resistance depends on the orientation of the mer operon within hlyA, with the highest level being observed for the orientation found in CVD103-HgR; (iii) no DNA sequences from plasmids used in construction remain in the genome; (iv) the strain is genetically stable; and (v) both CVD103-HgR and its parent strains contain defective lysogenic prophages. We have further confirmed that a certain amount of restriction fragment length polymorphism (RFLP) exists around the chromosomal ctx locus within V. cholerae strains of the classical biotype (detectable on chromosomal DNA restricted by either HindIII or EcoRI, but not PstI).     

The first British reference preparations of cholera vaccine (Inaba) and of cholera vaccine (Ogawa)

We examined the visceral blood flow distribution during infusion of three vasodilators at doses that produced similar depression of systemic arterial pressure. The studies were performed in pentobarbital-anesthetized dogs using the radioactive microspheres technique. Minoxidil did not alter renal, total visceral, or visceral organ flow distribution with the exception of a modest increase in relative stomach blood flow. Nitroprusside increased the percentage of total visceral flow to the spleen and the hepatic artery. Dopamine increased blood flow to the stomach, intestine, and kidney. After phenoxybenzamine, the augmentation of stomach blood flow by dopamine was greatly increased, while blood flow to the splenic, pancreatic, and hepatic arteriolar vascular beds decreased. The decreases in blood flows may be due to decreased perfusion pressure in the absence of active vasodilation or to myogenic or metabolic autoregulation. Thus, at equivalent hypotensive responses, the vasodilator compounds that we studied produced markedly different patterns of visceral blood flow.     

Kinetics of local and systemic immune responses to an oral cholera vaccine given alone or together with acetylcysteine

Disruption of the hydrogen bonding network at the interface of Escherichia coli transaldolase by substitution of R300 to a glutamic acid residue resulted in a monomeric enzyme at basic pH values, with almost no change in the kinetic parameters. The stability of the R300A and R300E mutants towards urea and thermal inactivation is similar to that of the wild-type enzyme. X-ray analysis showed that no structural changes occurred as a consequence of the side chain replacement. This indicates that the quaternary structure is not required for catalytic activity nor does it contribute significantly to the stability of the enzyme. The results are not consistent with a proposed half-of-the-sites reaction mechanism.     

Effects of doxycycline in actively purging cholera patients: a double-blind clinical trial

In 51 actively purging cholera patients the efficacy of doxycycline, a long-acting tetracycline, was compared with a placebo and tetracycline hydrochloride. Seventeen patients who were given doxycycline at the recommended dose of 2 mg/kg at the beginning of the study, at 12 h, and at the repeated dose once daily purged a mean volume of 5.1 liters of stool and received an average of 5.7 liters of intravenous fluid. Nineteen patients receiving the placebo purged 10.1 liters of stool and received 9.7 liters of fluid. Fifteen patients given tetracycline hydrochloride at 6-h intervals passed 4.8 liters of stool and received 5.5 liters of fluid. The durations of diarrhea calculated in 8-h periods were 3.5, 8.0, and 4.1 h in the respective groups receiving doxycycline, placebo, and tetracycline. The differences between the doxycycline and placebo treatments and the tetracycline and placebo treatments were statistically significant. Those receiving doxycycline became vibrio-free in about 3 days as compared with 2 days for those receiving tetracycline; the group given the placebo were vibrio positive for the duration of their hospitalization. The results show that in the treatment of cholera the administration of doxycycline once daily has effects equal to those when tetracycline is administered at 6-h intervals. This is a distinct advantage because it decreases the demand on nursing personnel in epidemics. Also, doxycycline may be safely administered in cases of suspected renal failure from prolonged shock in cholera.     

CSP生产低碳铝镇静钢的钙处理

通过对国内某钢厂CSP工艺生产的低碳铝镇静钢钙处理前后钢中夹杂物类型的变化研究,从热力学上分析了钢中Al2O3夹杂物的变性机理及夹杂物中wCaS较高的原因。同时,重点描述了钢中夹杂物不同类型的发展过程和夹杂物中CaS的存在形式。研究结果表明,钙处理后钢中镁铝尖晶石和钢中Ca、S元素会结合并相互扩散;且在现有工艺条件下,钢中wS过高使钢液钙处理后钢中原有的高熔点镁铝尖晶石夹杂物没有转变为低熔点夹杂物,同时也是钢中生成了大量CaS的主要原因;在现有工艺水平下,钢中wT[Ca]应控制在0.001 4%~0.002 8%较为合适。     

Field trial of a vaccine against New World cutaneous leishmaniasis in an at-risk child population: safety, immunogenicity, and efficacy during the first 12 months of follow-up

The safety, immunogenicity, and efficacy of a vaccine against cutaneous leishmaniasis in rural Ecuadorian children was assessed in a randomized, controlled, double-blinded study. Vaccine group subjects received 2 intradermal doses of a whole, killed promastigote vaccine cocktail plus bacille Calmette-Guérin (BCG) adjuvant. Control subjects got 2 doses of BCG only. The subjects who received both vaccination doses, 438 in the vaccine group (79.3%) and 406 in the control group (83.4%), were followed for 12 months. No serious adverse side effects were identified in either group. Significantly more vaccine group subjects than controls converted to a positive Montenegro skin test (85.1% vs. 20.1%; chi2 = 279; P < .001). The incidence of cutaneous leishmaniasis was significantly reduced in the vaccine compared with the control group (2.1% vs. 7.6%; chi2 = 8.95; P < .003). The protective efficacy of the vaccine was 72.9% (95% confidence interval = 36.1%-88.5%).     

High-dose epirubicin in locally advanced operable noninflammatory breast cancer: a feasibility trial

AIMS AND BACKGROUND: Anthracyclines are among the most active agents for the treatment of patients with locally advanced breast cancer. The aim of our study was to evaluate the feasibility and activity of a relatively high-dose regimen with 4-epirubicin plus normal doses of cyclophosphamide over a short period of time without the use of hematologic growth factors as adjuvant in resected locally advanced breast cancer. METHODS: Between January 1990 and June 1992, 43 consecutive patients, premenopausal or postmenopausal < 60 yrs, were surgically resected and then treated with epirubicin plus cyclophosphamide for at least 4 cycles (maximum 6). Electron beam (6-10 MeV energy) radiotherapy was delivered on the chest wall in patients with pathological skin infiltration (pT4b). RESULTS: Median age was 46 years (range, 27-59); 37 were premenopausal and 6 postmenopausal. The total number of administered cycles was 202 (6 in 15 patients and 4 in 28 patients); 195/202 (96.5%) were administered at full dose, and 7 (3.5%) were reduced to 75% of the planned dosage. The three-year disease-free survival was 67% for stage IIIa and 61% for stage IIIb patients. The three-year overall survival was 88% and 79%, respectively. Local relapse only was reported in one patient (2%), distant relapse in 11 patients (25%), and local and distant relapse in four patients (9%). Toxicity was acceptable and mainly hematologic. CONCLUSIONS: Our trial showed that the regimen is feasible without the use of hematologic growth factors. In this era of cost containment, the use of this short-term, high-dose induction course instead of repetitive courses of conventional dose regimens merits further evaluation, possibly in a large randomized trial.     

Effect of topical oral G-CSF on oral mucositis: a randomised placebo-controlled trial

Oral mucositis is a dose-limiting toxicity of intensive chemotherapy. It is caused directly by the cytotoxic effect of chemotherapeutic agents and indirectly by sustained neutropenia. Severe oral mucositis is an important predisposing factor for life-threatening septic complications during aplasia. It also reduces quality of life. At present, no effective causal prophylaxis or treatment against oral mucositis is established. We performed a prospective randomised placebo-controlled trial using topical oral r-metHuG-CSF (filgrastim) in high-grade lymphoma patients treated according to the B-NHL protocol, which contains high-dose methotrexate and causes severe oral mucositis (WHO grades I-IV) in >50% of patients. Between August 1996 and July 1997, a total of 32 chemotherapy cycles were documented in eight patients (four male, four female). Mucosal erythema and ulceration were recorded. All patients assessed their oral pain and impact on swallowing daily, using a subjective scale from no to maximal discomfort (1-10). In addition, oral mucositis was assessed according to the WHO score. Filgrastim was administered in 16 cycles as a viscous mouthrinse (carboxymethylcellulose 2%, oleum citrii) 4 x 120 microg/day from days 10 to 16. Sixteen cycles were given to control patients, of these 14 with placebo, and another two cycles with no treatment. Severe mucositis (WHO grade III/IV) was documented in 21 of 32 cycles (65.5%). A difference of borderline significance was observed for the reduction of maximum severity of oral mucositis between G-CSF vs placebo (P = 0.058), with a reduction of WHO grade IV of 50% (four G-CSF vs eight control). The number of days in hospital was reduced significantly in the G-CSF group (P = 0.02). In conclusion, topical oral G-CSF mouthrinses may be beneficial to reduce oral mucositis.     

Preliminary assessment of the safety and immunogenicity of a new CTXPhi-negative, hemagglutinin/protease-defective El Tor strain as a cholera vaccine candidate

Vibrio cholerae 638 (El Tor, Ogawa), a new CTXPhi-negative hemagglutinin/protease-defective strain that is a cholera vaccine candidate, was examined for safety and immunogenicity in healthy adult volunteers. In a double-blind placebo-controlled study, no significant adverse reactions were observed in volunteers ingesting strain 638. Four volunteers of 42 who ingested strain 638 and 1 of 14 who received placebo experienced loose stools. The strain strongly colonized the human small bowel, as evidenced by its isolation from the stools of 37 of 42 volunteers. V. cholerae 638, at doses ranging from 4 x 10(7) to 2 x 10(9) vibrios, elicited significant serum vibriocidal antibody and anti-Ogawa immunoglobulin A antibody secreting cell responses.     

Renal effects of oral prostaglandin supplementation after ibuprofen in diabetic subjects: a double-blind, placebo-controlled, multicenter trial

Prostaglandins of the E series (PGE) are known to contribute to the maintenance of renal hemodynamics in subjects with chronic renal insufficiency. Agents that block PGE synthesis, nonsteroidal anti-inflammatory agents (NSAID), are widely used by people with renal insufficiency. This study was undertaken in subjects with renal insufficiency secondary to diabetes to evaluate the acute effects of a PGE1 analog, misoprostol, on NSAID-induced changes in RBF, as calculated by para-aminohippurate clearance, and GFR, as calculated by inulin clearance. Sodium excretion was also assessed. Twenty-five fasting subjects with a mean age of 56 +/- 4 yr received 800 mg of ibuprofen orally. A concomitant dose of either a placebo (PL) or 200 micrograms of misoprostol was also given. This was followed in 1 h by either a placebo or an additional 200-micrograms dose of misoprostol. Measurements for the determination of RBF, GFR, blood pressure, and fractional excretion of sodium were performed every 30 min for the next 5 h. The greatest reduction in both GFR (-25 +/- 7 mL/min per 1.73 m2 PL versus -10 +/- 4 mL/min per 1.73 m2, misoprostol delta GFR; P < 0.05) and RBF (-48 +/- 21 mL/min per 1.73 m2 PL versus -15 +/- 8 mL/min per 1.73 m2, M delta RBF; P < 0.05) occurred approximately 2 h after the NSAID dose. No significant differences were noted in blood pressure, fractional excretion of sodium, or other measured parameters between groups during the entire study. Gastrointestinal upset was the most common side effect observed in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella typhi as a liver oral vaccine

A mutant (Ty21a) of Salmonella typhi, which lacks the enzyme uridine 5'-diphosphate-glucose-4-epimerase, was evaluated in volunteers for use as a live attenuated oral typhoid vaccine. Five to eight doses of vaccine (containing 3-10(10) viable organisms per dose) were given to 155 men without significant side effects. The rate of excretion of the vaccine strain in stools was low, and the majority of isolations occurred on day 1 after vaccination. Revertants able to fement galactose were not found in any of 958 stool isolates tested. The mutant, strain Ty21a, grown in brain-heart infusion broth (BHIB) with 0.1% galactose, produces more O side chain than the same vaccine strain cultivated without galactose. Volunteers vaccinated with strain Ty21a grown in galactose and then challenged with 10(5) virulen S. typhi were significantly protected from disease and also had decreased stool carriage of S. typhi as compared with controls. Strain Ty21a grown without galactose did not provide vaccinees significant protection nor decrease fecal excretion of S. typhi as compared with controls. Strain Ty21a, when grown in BHIB with 0.1% galactose, results in a safe, stable and protective oral vaccine that warrants further study in field trials.     

Protective immunity induced by oral immunization with a rotavirus DNA vaccine encapsulated in microparticles

DNA vaccines are usually given by intramuscular injection or by gene gun delivery of DNA-coated particles into the epidermis. Induction of mucosal immunity by targeting DNA vaccines to mucosal surfaces may offer advantages, and an oral vaccine could be effective for controlling infections of the gut mucosa. In a murine model, we obtained protective immune responses after oral immunization with a rotavirus VP6 DNA vaccine encapsulated in poly(lactide-coglycolide) (PLG) microparticles. One dose of vaccine given to BALB/c mice elicited both rotavirus-specific serum antibodies and intestinal immunoglobulin A (IgA). After challenge at 12 weeks postimmunization with homologous rotavirus, fecal rotavirus antigen was significantly reduced compared with controls. Earlier and higher fecal rotavirus-specific IgA responses were noted during the peak period of viral shedding, suggesting that protection was due to specific mucosal immune responses. The results that we obtained with PLG-encapsulated rotavirus VP6 DNA are the first to demonstrate protection against an infectious agent elicited after oral administration of a DNA vaccine.     

Long-term follow-up of a randomized trial on adjuvant chemotherapy and hormonal therapy in locally advanced breast cancer

Epidemiological research on respiratory syncytial virus (RSV) infections in children was carried out at the Virology Laboratory, University Teaching Hospital (UTH), in Lusaka, Zambia, from January-December 1996. Specimens including 736 nasal washings and 2424 throat swabs were collected from children with acute respiratory infections (ARI) and tested for RSV by enzyme immunoassay and by virus isolation. RSV was isolated in 62 (4.1%) of 1496 throat swabs collected from March to September and was detected in 99 (16.3%) of 609 nasal washings from March to November. The average RSV isolation rate was 2.6% and the average RSV detection rate was 13.5%. The highest RSV isolation (8.1%) and detection (30.5%) rates were in June 1996. RSV antibody in the 278 serum specimens collected from Zambian children, who were hospitalized in the paediatric ward, UTH, was detected using a standard neutralization test. The antibody positive rate was 60-80% in children > 4 years. It is evident that RSV is one of the main causal agents of ARI in children in Zambia.     

Pasteurella challenge and ELISA serology evaluation of broiler breeders vaccinated with live cholera vaccine

A novel high-pressure, high-resolution NMR probe is described which operates at a frequency of 500 MHz. The design features an alternative RF coil (8 mm sample tube) for high frequency, sensitivity, probe power, and resolution (< 3.0 x 10(-9)). The probe is capable of pressures to at least 5 kbar over a temperature range of -30 to 80 degreesC, and has a double-tuned 1H/2H circuit which can tune at 1H frequencies of either 300 or 500 MHz. The sensitivity of the 300-MHz circuit is over twice that of previous 10-mm high-pressure NMR probe designs, while at 500 MHz the sensitivity is nearly five times that of previous 300-MHz pressure probes. Potential biochemical applications are demonstrated by 2D NOESY spectra of a Troponin C mutant.