Immunogenicity, safety and tolerability of varying doses and regimens of inactivated hepatitis A virus vaccine in Navajo children.

The Navajo are known to be at high risk for hepatitis A virus (HAV) infection. This study investigated the safety and immunogenicity of an investigational, alum-adjuvanted, formalin-inactivated HAV vaccine (VAQTA) developed by Merck Research Laboratories in Navajo children. One hundred two of 212 children, ages 4 to 12 years, were HAV-seronegative (< 10 mIU/ml by an enhanced sensitivity modification of the HAVAB; Abbott). Ninety of these children received the HAV vaccine. Study participants were given vaccines containing various viral protein concentrations: Group A (n = 18), 6 units; Group B (n = 36), 13 units; and Group C (n = 36), 25 units HAV protein (1 unit approximately 1 ng viral protein antigen). Three-dose (0, 8, 24 weeks) and two-dose (0, 24 weeks) regimens were compared in subgroups within B and C. The vaccine was well-tolerated and there were no serious adverse reactions; no vaccinee developed hepatitis A. After 1 dose 82 to 100% of children seroconverted (> or = 10 mIU/ml, modified HAVAB; Abbott) and 100% seroconverted after 2 doses. After 1 dose the geometric mean titer for antibody was: Group A, 22 mIU/ml; Group B, 18 mIU/ml; and Group C, 38 mIU/ml. After 3 doses geometric mean titers increased to 10,106 mIU/ml in Group A, 7258 mIU/ml in Group B and 11,856 mIU/ml in Group C. Further field studies are indicated to evaluate its use in high risk populations, such as the Navajo.

Rehydration and nutritional management.

Diarrhoea remains a leading worldwide cause of morbidity and mortality. In developing countries alone, 1.5 billion episodes of diarrhoea occur per year in children under 5 years of age and approximately 4,000,000 of these result in death. Early, appropriate therapy decreases the risk of complications and death due to diarrhoea. Regardless of the causative agent, oral rehydration and nutritional management are the mainstays of good management of infants, children and adults with diarrhoea. Diarrhoeal disease control programmes throughout the developing world have adopted the WHO case management plan as a standard. In this chapter, we review the history, successes and shortcomings of various oral rehydration therapies and recommend a case management approach that is similar to the WHO plan. Although ORT is safe, effective, convenient and economical, this therapy has not been universally implemented in health care settings. The challenge for clinical and public health practitioners in developing and developed countries is to identify and overcome the barriers that exist so that all patients with diarrhoea will have the opportunity to receive optimal care.

Prevention of Haemophilus influenzae type b infections in Apache and Navajo children.

Prospective surveillance of Haemophilus influenzae type b (Hib) disease has been done since 1981 in two high-risk populations, White Mountain Apaches and Navajos. The attack rate in children less than 5 years of age is 5-10 times higher than in the general US population. Three vaccines were evaluated. Unconjugated Hib capsular polysaccharide produced lower antibody responses in 18- and 24-month-old Apache infants than in white infants. HbOC (Hib oligosaccharide covalently linked to the nontoxic mutant diphtheria toxin CRM197) produced low antibody responses in Navajo infants after one or two doses but induced responses similar to those in whites after three doses. The responses of 18-month-old Navajos to HbOC were lower than those of whites, but most achieved protective levels. PRP-OMP (Hib capsular polysaccharide linked to the outer membrane protein complex of Neisseria meningitidis) produced good immune responses in 2-month-old Navajo and Apache infants after a single dose. This vaccine was greater than 90% efficacious in protecting Navajo infants from Hib disease when given at 2 and 4 months of age. Even a single dose achieved a high protective efficacy.

Interaction of ultrasonic hyperthermia with two alkylating agents in a murine bladder tumor.

Fischer rats bearing s.c. implants of TCT-4909 bladder tumor were treated either with ultrasonic hyperthermia (US) (44.2 degrees, 20 min) or either of two alkylating agents, thiotepa or Cytoxan (CTX) or in combinations of chemotherapeutic agent and heat at specific time intervals. Applying US 20 hr before either agent (thiotepa, 2 mg/kg i.p.; or CTX, 50 mg/kg i.p.) had a less than additive effect upon tumor growth. CTX, administered 20 hr before US, resulted in a significantly increased tumor volume-doubling time compared to CTX only. This was not true for thiotepa. With both agents, a synergistic effect was obtained when US and the agent were applied within 1 hr of each other, but the maximum was observed when the US had been applied 30 min before injection of agent. The intratumor temperature had decayed to normal at the time of injection. Radiolabeled alkylating agents injected at different times after US showed decreased uptake of label up to 20 hr after heating. Tritiated thymidine uptake was also reduced over the same period. Nuclear morphometry indicated increased nuclear condensation in parallel with the reduced uptakes described above. The data suggest that the synergism was not due to increased uptake of agent into heated tissue nor to the direct activation of alkylating activity by heat. It was demonstrated that heat had a rapid and marked inhibitory action upon DNA synthesis. This could have augmented the delayed but prolonged DNA inhibition caused by the alkylating agents to produce a synergistic effect. The apparent prolongation of the growth-inhibitory effect of CTX or thiotepa by heat may be due to the thermal inhibition of the enzymes responsible for the recovery of DNA after alkylation. The precise mechanism for the synergy may vary with the agent, the dose, the equilibrium temperature and its dwell time, and the interval between modalities. The influence of each of these parameters will require further investigation.

Diagnostic problem in acute myocardial infarction: CK-MB in the absence of abnormally elevated total creatine kinase levels.

Seven hundred twenty-four consecutive patients admitted to a coronary care unit for chest pain underwent comparative evaluation of ECG and lactic dehydrogenase (LDH) and creatine kinase (CK) enzyme and isoenzyme patterns. Of the 724 patients, 419 (58%) had the myocardial component (MB) of CK detected; however, 69 (16%) of the latter had no abnormal elevation of total CK levels. This group with CK-MB but persistently normal total CK levels demonstrated fewer diagnostic QRS changes on ECG (17% vs 54%) and a lower incidence of LDH 1:2 inversion (28% vs 79%) than did the group with CK-MB and abnormally elevated total CK levels. However, no specific level of either total CK or CK-MB could segregate the patients with QRS or LDH level changes, which suggests that persistently normal levels of CK do not exclude the diagnosis of myocardial infarction. Evidence that myocardial necrosis can occur in the absence of an abnormal elevation of total CK levels is confirmed histologically in one patient.

Ultrasonic hyperthermia system for tumor irradiation.

A laboratory ultrasonic exposure system has been developed to investigate practical energy regimes and equipment that will provide a modality for producing irreversible ultrastructural and biochemical changes to animal tumors in vivo. Electric energy is made available over a wide range of power levels and frequencies. This energy is converted to sonic pressure energy by piezoelectric element transducers. The transducer is an applicator that transmits a collimated or focused energy field to irradiate the tumor target area. That energy absorbed by the tumor gives rise to a spatial temperature distribution. Using their primary laboratory delivery system, the authors treated subcutaneous tumors in rats at controlled levels of energy and temperature. The results indicate that there are thresholds of applied energy and base temperatures above which substantial tumor damage can be expected. Histological examination supported by biochemical analysis reveals irreversible ultrastructural and chemical changes.

The direct effect of ultrasound upon Wilms' tumor in the rat.

The possible activation of immunologic defenses against tumor by local ultrasonic irradiation was investigated. Sonication of one tumor of a dual implant destroyed that tumor only with no contralateral effect. Injection of tumor cells previously sonicated in vivo did not induced immunity to subsequent challenge with live cells. Immunofluorescent staining of host kidneys for antibody complexes was negative. It was concluded that sonication was only effective when directly applied to the tumor.

Interaction of ultrasound with neoplastic tissue. II. Systemic effects after local sonic irradiation.

Local sonic irradiation was applied to subcutaneously implanted Furth-Columbia rat Wilms' tumor. The weight and the rate of tritiated thymidine uptake were measured in host organs distal to the application field. Kidney and spleen weights were inhibited by the Wilms' tumor, and sonication of the tumor removed all or part of this inhibition. Liver weight was increased after sonication of tumor-bearing rats but not in nontumor-bearing rats. This may have been a response to tumor-specific substances released into the circulation by sonic destruction of tumor tissue. The adrenals enlarged as a response to the stresses of both tumor-bearing and of sonication. Animals were implanted on both sides with the Wilms' tumor and on without any break in the growth curve while the sonicated right tumor was inhibited. These data suggest that the therapeutic effect of ultrasound is due solely to local factors and that systemic sequelae of some irradiation are unrelated to tumor inhibition.

Interaction of ultrasound with neoplastic tissue. III. Electron microscopic demonstration of ulstrasonic destruction of Wilms tumor and its cellular membranes.

Exposure of 300 adult, male Wistar-Furth rats bearing subcutaneous implants of Wilms tumor to a vertically oriented planar ultrasound beam consistently resulted in a marked decrease in the growth rates of the tumors with an increase in the survival times of the treated animals. Grossly, the local effects consisted of a flattening of the tumors with clean excavation of their bases. Histologically, a line of demarcation was demonstrated between the sonicated (or destroyed) and non-sonicated portions of the same rat Wilms tumors. The sonicated portions exhibited a complete loss of the normal spatial relationship between the tumor epithelium and its surrounding mesenchyme. Ghost residuals of portions of individual cytoplasmic cell borders and nuclei with condensed chromatin patterns still could be discerned. Electron microscopy demonstrated a marked destruction of the nuclear and cytoplasmic cellular membranes with a migration of destroyed condensed chromatin material into the surrounding cytoplasm.

Interaction of ultrasound with neoplastic tissue. Local effect on subcutaneously implanted Furth-Columbia rat Wilms' tumor.

Ultrasonic irradiation was employed by direct administration to the skin overlying subcutaneously implanted Furth-Columbia rat Wilms' tumors. Treated tumors were flattened and excavated and demonstrated no stigmata of hemorrhage or infection. There was a marked decrease in growth rate of the tumors with an increase in survival time of the host. Histologic assessment with the light microscope exhibited a sharp line of demarcation between the necrosed sonicated portion of tumor and the viable intact nonsonicated area of tumor. A blackened area of skin, which was not histologically similar to a burn, was interposed betwwen the site of application of the ultrasound and the necrosed tumor.