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PubMed1996

Nonsensitizing causes of occupational asthma.

Irritant-induced asthma and RADS are related conditions that need further study focusing on the following questions: (1) Are there differences between the pathologic and functional features that follow single or multiple exposures to an irritant material? (2) What is the time course of the changes? (3) What are the physiologic correlates in terms of onset of airway hyperresponsiveness? (4) What are the risk markers (besides exposure)? (5) Are there means of modulating the reaction by using anti-inflammatory preparations? Developing an animal model of irritant-induced asthma and conducting prospective epidemiologic surveys in high-risk workers may be most effective routes to provide satisfactory answers to these questions. Further examination of the physiopathology of such conditions as byssinosis, grain-dust-induced respiratory disease, and aluminum potroom asthma as well as of the differences from and similarities to OA is also warranted.

Asthma↗
PubMed2002

Uranyl acetate-induced sensorimotor deficit and increased nitric oxide generation in the central nervous system in rats.

We investigated the effects of uranyl acetate on sensorimotor behavior, generation of nitric oxide and the central cholinergic system of rats. Male Sprague-Dawley rats were treated with intramuscular injection of 0.1 and 1 mg/kg uranyl acetate in water, daily for 7 days. Control animals received equivalent amount of water. The treatment was stopped after the seventh injection because the animals in the 1-mg/kg group appeared lethargic. The animals were maintained for an additional observation period of 30 days. The study was initiated as a dose-finding study that covered doses of 10 and 100 mg/kg, as well. However, all the animals in the 100-mg/kg treatment group died after the third and fourth injections, and all animals given 10 mg/kg died after the fifth and sixth injections. On Day 30 following the cessation of treatment, the sensorimotor functions of the animals in the 0.1- and 1-mg/kg treatment groups were evaluated using a battery of tests that included measurements of postural reflexes, limb placing, orientation to vibrissae touch, grip time, beam walking and inclined plane performance. The animals were sacrificed the same day and the cerebral cortex, brainstem, cerebellum and midbrain were dissected. The levels of nitric oxide as marker for increased oxidative stress, and the integrity of the cholinergic system as reflected in acetylcholinesterase (AChE) activity and m2 muscarinic acetylcholine receptors ligand binding, were determined. The data from behavioral observations show that there was a dose-related deficit at the 0.1- and 1-mg/kg treatment groups for inclined plane performance. Both doses reduced grip time, but there was no significant difference between the two doses. Similarly, both beam-walk score and beam-walk time were impaired at both doses as compared with the controls. A significant increase in nitric oxide was seen at 0.1 mg/kg dose in cortex and midbrain, whereas brainstem and cerebellum showed an insignificant decrease at both the doses. Similarly, there was no significant change in nitric oxide levels in kidneys and liver of the treated animals as compared with the controls. There was a significant increase in AChE activity in the cortex of the animals treated with 1 mg/kg uranyl acetate, but not in other brain regions. Ligand binding densities for the m2 muscarinic receptor did not show any change. These results show that low-dose, multiple exposure to uranyl acetate caused prolonged neurobehavioral deficits after the initial exposure has ceased.

Acetylcholinesterase↗
PubMed2003

How to teach evidence-based medicine.

Learning to practice EBM provides physicians with the tools needed to overcome some of the common barriers they face when trying to use the medical literature to solve patient problems. It does require a change in attitude and behavior and is likely to be met with some resistance. Understanding the learners' stage of behavior change is likely to facilitate educational intervention. Behavior change does not occur unless physicians are convinced of the benefits of practicing EBM. Easy access to evidence-based summaries facilitates the use of high-quality evidence. Developing the ability to access information from the medical literature, critically appraising it, and applying it to patient care requires skills that need to be taught. Most practicing physicians were not taught these skills in medical school. Excellent resources are available from which to learn and teach EBM. Multiple exposures using a variety of formats are most effective. Finally, a tool to evaluate the acquisition of knowledge and skills needed to practice EBM recently has been validated. Despite ongoing challenges, learning and teaching EBM has never been easier and each year brings new and better tools to help practitioners and educators use the best available evidence. Box 2 lists suggestions for getting started.

Education, Medical↗
PubMed1998

HIV-1-resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene.

BACKGROUND: Despite multiple exposures to HIV-1, some individuals remain uninfected, and their peripheral-blood mononuclear cells (PBMC) are resistant to in-vitro infection by primary HIV-1 isolates. Such resistance has been associated with a homozygous 32-base-pair deletion (delta 32) in the C-C chemokine receptor gene CCR5. We examined other mutations of the CCR5 gene that could be associated with resistance to HIV-1 infection. METHODS: We assessed the susceptibility of PBMC to in-vitro infection by HIV-1 isolates that use the CCR5 as the major coreceptor for viral entry in 18 men who had frequent unprotected sexual intercourse with a seropositive partner. We also did genotypic analysis of CCR5 alleles. One of the 18 exposed but uninfected men (who we refer to as ExU2) showed total resistance to in-vitro infection by CCR5-dependent viruses, and was found to carry a CCR5 delta 32 allele and a single point mutation (T-->A) at position 303 on the other allele. To find out whether the CCR5 mutation was restricted to ExU2's family or existed in the general population, we did genetic analyses of the CCR5 genotype in ExU2's father and sister and also in 209 healthy blood donors who were not exposed to HIV-1. FINDINGS: The m303 mutation found in ExU2 introduced a premature stop codon and prevented the expression of a functional coreceptor. The family studies revealed that the m303 mutant allele was inherited as a single mendelian trait. Genotype analysis showed that three of the 209 healthy blood donors were heterozygous for the mutant allele. INTERPRETATION: We characterise a new CCR5 gene mutation, present in the general population, that prevents expression of functional coreceptors from the abnormal allele and confers resistance to HIV-1 infection when associated to the delta 32 CCR5 mutant gene.

Acquired Immunodeficiency Syndrome↗
PubMed1997

The effect of dexamethasone on immunological memory to tetanus toxoid in sheep.

One of two groups of sheep was immunosuppressed with the glucocorticoid, dexamethasone, at the time of the first but not of the second of two booster vaccinations with tetanus toxoid given at an interval of 28 days. Treatment with dexamethasone decisively reduced the anti-tetanus antibody response to the first booster vaccination and affected both IgM and IgG1 antibody. However, antibody titres increased after the second booster vaccination in the treated sheep and were similar in size to those in the untreated sheep which rose in stepwise fashion after each booster vaccination. The differences in response imply that processes involved in displaying an anamnestic response and recalling previously established memory are sensitive to glucocorticoids. Accordingly, they can be separated from the glucocorticoid-resistant processes that lead to the expansion of immunological memory following multiple exposures to an antigen.

Animals↗
PubMed2003

Joint algal toxicity of 16 dissimilarly acting chemicals is predictable by the concept of independent action.

For a predictive assessment of the aquatic toxicity of chemical mixtures, two competing concepts are available: concentration addition and independent action. Concentration addition is generally regarded as a reasonable expectation for the joint toxicity of similarly acting substances. In the opposite case of dissimilarly acting toxicants the choice of the most appropriate concept is a controversial issue. In tests with freshwater algae we therefore studied the extreme situation of multiple exposure to chemicals with strictly different specific mechanisms of action. Concentration response analyses were performed for 16 different biocides, and for mixtures containing all 16 substances in two different concentration ratios. Observed mixture toxicity was compared with predictions, calculated from the concentration response functions of individual toxicants by alternatively applying both concepts. The assumption of independent action yielded accurate predictions, irrespective of the mixture ratio or the effect level under consideration. Moreover, results even demonstrate that dissimilarly acting chemicals can show significant joint effects, predictable by independent action, when combined in concentrations below individual NOEC values, statistically estimated to elicit insignificant individual effects of only 1%. The alternative hypothesis of concentration addition resulted in overestimation of mixture toxicity, but differences between observed and predicted effect concentrations did not exceed a factor of 3.2. This finding complies with previous studies, which indicated near concentration-additive action of mixtures of dissimilarly acting substances. Nevertheless, with the scientific objective to predict multi-component mixture toxicity with the highest possible accuracy, concentration addition obviously is no universal solution. Independent action proves to be superior where components are well known to interact specifically with different molecular target sites, and provided that reliable statistical estimates of low toxic effects of individual mixture constituents can be given. With a regulatory perspective, however, fulfilment of both conditions may be regarded as an extraordinary situation, and hence concentration addition may be defendable as a pragmatic and precautionary default assumption.

Algorithms↗
PubMed1994

Mycobacterial infection in guinea pigs.

We described published reports of the chaos which exists in research concerning laboratory animal models for assay of tuberculosis (TB) vaccines and proposed a "rational animal model" as a solution to the problem. This animal model, an aerosol challenge model in guinea pigs, was recently applied to the problem of differences in growth characteristics of sputum isolates of low and high virulence. The same model was used to investigate the protective effect of high dose BCG given aerogenically. Based on studies in the guinea pig model of experimental airborne TB, and a review of the literature on pathogenesis of human TB, we described an "integrated model" for the pathogenesis of TB, a model which includes a role for both the endogenous reactivation and the exogenous reinfection pathways. Our hypothesis is that tubercle bacilli must be able to gain access to the "vulnerable region" in the lung apex in order to survive the effects of the CMI response. In endogenous reactivation TB (virulent tubercle bacilli), this access occurs via the bloodstream. Whereas in exogenous reinfection TB, access to the vulnerable region occurs via multiple exposures via the respiratory tract. Central to our perspective is the acceptance of the evidence that during first infection with virulent organisms, tubercle bacilli enter the bloodstream via the efferent lymphatics. We believe the hypotheses we have proposed have the potential to lead to a further increase in our knowledge of these mechanisms and are a prerequisite to studies aimed at the development of new vaccines.

Animals↗
PubMed2002

Identification of antigenically active tryptic fragments of apical membrane antigen-1 (AMA1) of Plasmodium chabaudi malaria: strategies for assembly of immunologically active peptides.

Apical membrane antigen-1 (AMA1) is a prime vaccine candidate for inclusion in a vaccine against malaria. It is known that the disulphide bond stabilised conformation of this antigen is important for eliciting a protective antibody response, however little is known about the epitopes within this molecule that are targeted by the immune response. We have used a peptide approach for the identification and characterisation of such regions. In this study, the in vitro refolded, recombinant ectodomain of AMA1 from the D strain of Plasmodium chabaudi adami, was digested with trypsin and individual peptide fragments examined for antigenic activity. We found that a tryptic fragment, which was derived from a loop-like structure within the putative domain I of the intact AMA1 molecule, was highly reactive with antibodies from the sera of hyperimmune mice. Two different synthetic peptide constructs incorporating this antigenically active fragment were assembled. The first consisted of two separate peptide chains which were linked through a disulphide bond formed using chemo-selective chemistry. A larger 45-mer loop peptide, generated by the oxidation of two cysteine residues close to the N- and C-termini of the 45-mer, represented the complete loop structure and incorporated the tryptic fragment. Each peptide construct was also able to elicit production of high titres of antibodies in mice and furthermore, the 45-residue loop peptide elicited antibodies capable of binding to AMA1 with titres comparable to those present in a mouse which had recovered from multiple exposures to P. chabaudi adami parasites. Passive immunisation with anti-loop antibodies did not suppress the development of parasitaemia in mice challenged with P. chabaudi adami suggesting that although highly immunogenic, the peptides represented inadequate or inappropriate epitopes for vaccination purposes.

Amino Acid Sequence↗
PubMed1988

Complications and monitoring of OKT3 therapy.

Complications of OKT3 therapy were studied in 122 treatment episodes in renal allograft recipients (83 for rejection treatment, 39 for immunosuppression induction). A febrile first-dose reaction to OKT3 was common; no severe pulmonary complications were encountered. Other toxicities of OKT3 therapy were observed later in the treatment course. Most severe were the occurrence of aseptic meningitis in four patients (3%), and seizures in eight (6%). Seizures occurred only when OKT3 was given to patients with nonfunctioning grafts due to acute tubular necrosis. Infections were the only significant late adverse sequelae of OKT3 therapy and occurred more frequently after multiple exposures to the drug (53%) than after a single exposure (22%). IgG antibodies to OKT3 developed after 45% of exposures to the drug in the 74 patients in whom appearance of anti-OKT3 antibodies was monitored. In two patients (3%), anti-OKT3 antibodies were detected before the end of the OKT3 treatment course, neutralizing the immunosuppressive property of the drug. In five patients (7%), strong anti-OKT3 antibody responses were present at the time of subsequent rejection, which precluded reuse of the drug. In 17 other cases, no or only a weak anti-OKT3 response was detectable at the time of rejection following initial OKT3 exposure. Retreatment with OKT3 was successful in reversing rejection in 15 cases (88%). No untoward sequelae were noted after reexposure to OKT3, except the high incidence of subsequent infections.

Adult↗
PubMed1999

Anesthesia for pediatric external beam radiation therapy.

BACKGROUND: For very young patients, anesthesia is often required for radiotherapy. This results in multiple exposures to anesthetic agents over a short period of time. We report a consecutive series of children anesthetized for external beam radiation therapy (EBRT). METHODS: Five hundred twelve children < or = 16 years old received EBRT from January 1983 to February 1996. Patient demographics, diagnosis, anesthesia techniques, monitoring, airway management, complications, and outcome were recorded for the patients requiring anesthesia. RESULTS: One hundred twenty-three of the 512 children (24%) required 141 courses of EBRT with anesthesia. Anesthetized patients ranged in age from 20 days to 11 years (mean 2.6 +/- 1.8 ). The frequency of a child receiving EBRT and requiring anesthesia by age cohort was: < or = 1 year (96%), 1-2 years (93%), 2-3 years (80%), 3-4 years (51%), 4-5 years (36%), 5-6 years (13%), 6-7 years (11%), and 7-16 years (0.7%). Diagnoses included: primary CNS tumor (28%), retinoblastoma (27%), neuroblastoma (20%), acute leukemia (9%), rhabdomyosarcoma (6%), and Wilms' tumor (4%). Sixty-three percent of the patients had been exposed to chemotherapy prior to EBRT. The mean number of anesthesia sessions per patient was 22 +/- 16. Seventy-eight percent of the treatment courses were once daily and 22% were twice daily. Anesthesia techniques included: short-acting barbiturate induction + inhalation maintenance (21%), inhalation only (20%), ketamine (19%), propofol only (12%), propofol induction + inhalation maintenance (7%), ketamine induction + inhalation maintenance (6%), ketamine or short-acting barbiturate induction + inhalation maintenance (6%). Monitoring techniques included: EKG (95%), O2 saturation (93%), fraction of inspired O2 (57%), and end-tidal CO2 (55%). Sixty-four percent of patients had central venous access. Eleven of the 74 children with a central line developed sepsis (15%): 6 of the 11 were anesthetized with propofol (55%), 4 with a short-acting barbiturate induction plus inhalation maintenance (36%), and 1 with inhalation alone (9%). Eight of the 11 (73%) received prior chemotherapy. CONCLUSION: Anesthesia was generally necessary at < or = 3 years, and rarely required at > 5 years of age. Sepsis associated with frequent use of the central venous access line was seen in 15% of the patients with these lines.

Anesthesia Recovery Period↗
PubMed1998

First report of a healthy Indian heterozygous for delta 32 mutant of HIV-1 co-receptor-CCR5 gene.

The beta-chemokine receptor, CCR5, is a major co-receptor for macrophage tropic non-syncytia-inducing isolates of HIV-1. Recently a 32 bp homozygous deletion in the coding region of CCR5 has been reported in a very small percentage (< 1%) of Caucasian individuals who remain uninfected, despite multiple exposure to the wild-type virus. This mutant allele in the heterozygous form (CCR5/32 ccr5) was readily detected in a normal unrelated Caucasian population of European heritage with varying frequencies (13-20%). However, when a large number of the non-Caucasian population (261 Africans and 423 Asians) were screened for the presence of this deleted allele, not a single case of either homozygous or heterozygous mutant for delta 32 allele of CCR5 was detected. We screened 100 normal individuals and found a single heterozygous case with an identical 32 bp deletion in CCR5 gene reported earlier, the rest possessed wild-type alleles. This deleted gene was inherited in Mendelian fashion among the family members of this individual. Thus, the frequency of this deleted allele in India among unrelated normal individuals is likely to be very low (< 1%). We observed a moderate transdominant effect of this mutant allele in a fusion assay. Finally, we show a significant inhibition of fusion of cell membranes when the 176-bp region of CCR5 was used as an antisense.

Alleles↗
PubMed1997

Homologous challenge of porcine reproductive and respiratory syndrome virus immunity in pregnant swine.

The clinical consequences of single or multiple exposure of pregnant gilts to porcine reproductive and respiratory syndrome virus (PRRSV) at various stages of gestation were determined. Thirty-three pregnant gilts were allotted to 6 experimental groups (5 to 7 gilts/group). Gilts of groups 1 to 5 were exposed to strain NADC-8 of PRRSV at the following times: group 1, gestation day (GD) 1; group 2, GDs 1 and 90; group 3, GD 30; group 4, GDs 30 and 90; group 5, GD 90. Virus exposure was by either intrauterine (GD 1) or oronasal (GDs 30 and 90) inoculation. Gilts of group 6 were kept as nonexposed controls. Gilts were either necropsied on or about GD 111 (groups 1 to 5) or were allowed to farrow (group 6). The detection of PRRSV in serum of fetuses and piglets (within 12 hof birth) was considered evidence of transplacental infection. Transplacental infection and virus-induced death were and were not confirmed for groups 3, 4, and 5 and for groups 1, 2, and 6, respectively. Collectively, the results indicated that intrauterine exposure to PRRSV at GD 1 was without clinical effect (groups 1 and 2) and provided protection against subsequent exposure to the same strain of virus at GD 90 (group 2). The highest incidence of transplacental infection and fetal death followed a single exposure to PRRSV at GD 90 (group 5).

Animals↗
PubMed1997

[Fatal hepatitis in a young child: probable role of halothane].

A 3-year-old boy, who underwent multiple anaesthetics including halothane in a short period of time, developed 3 days after the last operation abdominal pain, jaundice and fever. Laboratory tests showed hepatic failure, with cytolysis, cholestasis and eosinophilia. Tests for hepatitis A, B, C, CMV and EBV were negative. No other causes of postoperative jaundice were identified. Despite symptomatic treatment, the child died 5 days after the last anaesthetic. Post mortem liver biopsy showed massive hepatic necrosis. The authors discuss factors increasing the risk for halothane-hepatitis, especially multiple exposures.

Accidents, Traffic↗
PubMed1988

Intraocular lens damage from Nd:YAG laser pulses focused in the vitreous. Part II: Mode-locked lasers.

Damage can be induced within the interior of a plastic intraocular lens (IOL) by a mode-locked Nd:YAG laser when the beam's focus lies well behind the IOL. This type of damage, which has not been reported, is the result of cumulative, multiple exposures. The damage differs from that created by optical breakdown (plasma formation) within the plastic, which occurs only when the beam is focused within or near the IOL surface. This type of damage can be avoided clinically by minimizing the number of pulsed exposures along the same beam path.

Humans↗
PubMedDate not supplied

Effects of halothane reexposure in female mice and their offspring.

Female CBi mice subjected to multiple exposures to halothane inhalation anesthesia before mating were investigated for the potential effects of such intervention on a specific antibody response mounted by them and their offspring. An assessment of the toxicologic and reproductive performance of female mice undergoing anesthesia was also performed. Adult female mice received three episodes of halothane anesthesia at weekly intervals. Seventy-two hours after the last dose, mice were subjected to the following procedures: 1) study of the specific humoral immune response to sheep red blood cells (SRBC); 2) hematologic, hepatologic, and histopathologic studies; and 3) mating with syngeneic sires. Halothane-treated females had increased amounts of specific antibody secreting B cells, with liver studies showing evidence of microscopic fatty changes and decreased lipid peroxidation. Anesthesia did not alter reproductive performance but lowered offspring survival. Offspring displayed depressed antibody response after challenge with SRBC at weaning and at 60 d of age. The anti-SRBC antibody response that was found to be enhanced in halothane anesthetized females, seemed to be conversely impaired when studied in the offspring.

Anesthetics, Inhalation↗
PubMed1992

The distribution of atherosclerosis in the lower limbs.

Sixty-seven consecutive aortograms in non-diabetic patients were studied to establish the distribution of atherosclerosis in the arteries of 134 lower limbs. Prolonged filming and multiple exposures of the feet showed ankle vessels in 131 of the limbs (98%) and a pedal arch or collaterals in 126 (93%). In 51% of the limbs at least one of the calf arteries was occluded and only 24% had two patent arteries at ankle level. The pedal arch was complete in only 16%. The patency rate of the pedal arch was similar in all three symptom groups (p greater than 0.05). Two separate analyses were performed. The first was based on symptoms. Critical ischaemia was present in 18 limbs (13%), claudication in 69 limbs (52%) and 47 limbs were symptomless (35%). The second analysis was based on the sites of major occlusion. Occlusions were already present in 81% of the symptomless limbs, predominantly in the distal vessels. In limbs with claudication or critical ischaemia there were more occlusions above the knee (77 and 89%, respectively) than in limbs without symptoms (36%) (chi 2 = 27.60, p less than 0.001). Occlusion of the popliteal artery was significantly more frequent in the patients with symptoms of critical ischaemia (50%) than in either of the other two groups (chi 2 = 15.61, p less than 0.001). Atherosclerosis appears to develop in the small vessels of the calf and foot at an early stage. The extent of this involvement may influence the progression of symptoms and the outcome of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2002

Fabrication of a capillary immunosensor in polymethyl methacrylate.

A method for fabricating capillary-based immunosensors in a coupon milled from an inexpensive, commodity plastic (PMMA, plexiglass) is demonstrated. The key feature of the technique is the use of sol-gel technology to deposit a glass-like (Si [bond] OH) film on surfaces of the plastic capillary channels to facilitate antibody immobilization. The utility of this method was demonstrated in the context of continuous flow displacement immunosensors for the explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). These sensors exhibited sensitivity to low microg/l RDX concentrations and peak-to-peak signal variations that were generally less than 10% for multiple injections at a single RDX concentration. The useful lifetime of the coupons in these experiments was greater than 10 h even after multiple exposures to high (1000 microg/l) RDX levels. This sensor platform has the physical characteristics needed for a portable field instrument: small, light-weight, and rugged.

Biosensing Techniques↗
PubMed2003

Patient setup and verification for intensity-modulated radiation therapy (IMRT).

Intensity Modulated Radiation Therapy (IMRT) is now widely used in the radiation therapy community. The ability of IMRT to deliver complex dose distributions has allowed dose escalation to targets while sparing normal tissues. In IMRT the roles of the physicist, dosimetrist, and physician are changed. Inverse planning, which is inherent to IMRT, requires that the final dose solution be defined at the beginning of the planning process. The physician must define specific dose volume constraints for the target as well as normal tissues. The physicist and dosimetrist must evaluate the final plan and determine if it meets the goals of the treatment, even if it does not completely satisfy the initial constraints. Once a plan is decided upon, the ability of the clinic to safely and accurately deliver that plan to the patient must be confirmed. As with any new technology, IMRT has created a need for new quality assurance procedures. Here we describe our IMRT process from simulation through planning and treatment. By standardizing our simulations we have decreased setup times and decreased the threat of collisions. Comparison of pseudo-DRR's and multiple-exposure port films allows confirmation of patient positioning on the linac. Our treatment delivery quality assurance program using film and MOSFET detectors in a polystyrene phantom is also described. We provide insight on how to overcome some of the common problems encountered in treatment planning and delivery such as isocenter location, collision avoidance, table indexing, dose confirmation, and plan analysis.

Humans↗