Vaccine liability and safety revisited.
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Child↗
Biomedical subjects
G Evans
Publications and source records attributed to G Evans.
Angiotensinogen and angiotensin converting enzyme genotypes and carotid atherosclerosis: the atherosclerosis risk in communities and the NHLBI family heart studies.
BACKGROUND: Polymorphisms of the renin-angiotensin system are associated with cardiovascular pathology. Therefore, the association of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene and the T235 (methionine to threonine substitution) polymorphism of the angiotensinogen (AGT) gene with intima-media thickness of the carotid artery was investigated. METHODS AND RESULTS: Subjects were randomly selected from two centers participating in both the Atherosclerosis Risk in Communities (ARIC) and NHLBI Family Heart Studies. Probands were 45-64 years of age who were free of cardiovascular disease and had B-mode ultrasound measured carotid intima-media thickness. Multiplex polymerase chain reaction amplification was used to evaluate the ACE I/D and AGT T235 polymorphisms: genotype information was available on 495 and 475 participants, respectively. The frequencies of the ACE D and AGT T alleles were 0.56 and 0.52, respectively; 30% were homozygous for the ACE D allele, and 29% were homozygous for the AGT T allele. After adjustment for systolic blood pressure, antihypertensive medication use, diabetes, age, sex and LDL cholesterol, the mean intima-media thickness was 0.729, 0.732 and 0.721 mm in the ACE DD, ID, and II genotypes, respectively (partial F test 1.53, P = 0.22), and 0.727, 0.732 and 0.724 mm in the AGT MM, MT, and TT genotypes, respectively (partial F test 0.91, P = 0.40). Combining the genotypes for ACE and AGT, there were also no differences in intima-media thickness across the eight joint genotypes. CONCLUSION: We found no evidence that the ACE I/D and AGT T235 polymorphisms of the renin-angiotensin system were associated with carotid intima-media thickness in this population-based sample of middle-aged adults with no history of cardiovascular disease. The lack of an association between these variants and intima-media thickness may indicate that early atherosclerosis is mediated by factors other than these RAS polymorphisms.
Angiotensinogen↗
Vaccine risk communication.
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Adverse Drug Reaction Reporting Systems↗
An unusual case of carotid body tumour.
Carotid body tumours are uncommon but fascinating lesions, which arise from paraganglionic tissue at the bifurcation of the common carotid artery. We report the case history of a 40-year-old female patient who presented initially with a malignant left-sided tumour, followed by a right-sided tumour 17 years later. Although there is no known family history, it is likely, because of the bilateral tumours and the young age at presentation, that the tumour was inherited in this patient. The literature on carotid body tumours is reviewed, with particular emphasis on malignant and multiple tumours and their treatment. We discuss the recently elucidated mechanism of inheritance and its implications for affected patients and their families.
Adult↗
Time course of pronuclear formation and fertilisation after insemination in vitro and intracytoplasmic sperm injection of in vitro matured sheep oocytes.
The time course of sperm decondensation, oocyte activation, pronuclear formation and the possible causes of abnormalities after intracytoplasmic sperm injection (ICSI) and in vitro fertilisation (IVF) were examined. Frozen-thawed and pooled fresh semen from three different rams were washed and capacitated for ICSI or IVF. In vitro matured oocytes were cultured after sperm injection for 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 18, 21 and 23 h, and oocytes were cultured after in vitro insemination for the same times other than 18 and 23 h. All oocytes were cultured in bicarbonate-buffered synthetic oviduct fluid medium (BSOF) supplemented with 2% oestrous sheep serum. A total of 746 metaphase II oocytes were injected with a single spermatozoon and 986 oocytes were inseminated for IVF. The earliest oocyte activation after ICSI was observed at 0.5 h, when 14.8% of oocytes were in anaphase II; this was earlier than after IVF, when only 6.4% of the oocytes exhibited anaphase II 1 h after insemination. Decondensing spermatozoa were first observed 1 h after ICSI and 3 h after insemination for IVF. The earliest female and male pronuclei after ICSI were observed at 2 and 3 h respectively, while the female and male pronuclei after IVF were observed at 4 h after insemination. The overall fertilisation rate was lower after ICSI (28.6%) than IVF (70.4%) but the percentage of abnormal fertilisation was not different between ICSI (8.7%) and IVF (15.2%). It was concluded that the fertilisation events were more advanced for ICSI than IVF, using injection and insemination time as reference points. The formation of male and female pronuclei were asynchronous after ICSI, in contrast to IVF when they appeared simultaneously at 4 h. Abnormalities found in fertilisation after ICSI may therefore be induced by the injection technique.
Animals↗
Controlled, multidose, pharmacokinetic evaluation of two extended-release carbamazepine formulations (Carbatrol and Tegretol-XR).
A major limitation of conventional carbamazepine (CBZ) formulations is their pharmacokinetics, which typically require q.i.d. dosing. Two extended-release formulations of CBZ have been developed recently to support b.i.d. dosing. One, Carbatrol (CBTL) uses immediate-, extended-, and enteric-release beads in a capsule. The other, Tegretol-XR (TXR), uses an osmotic pump (Oros tablet). To our knowledge, this is the first head-to-head comparison of the multidose pharmacokinetics of these two new formulations. The objective of the study was to evaluate the pharmacokinetics of carbamazepine (CBZ) and CBZ-10,11-expoxide (CBZ-E) after multidose b.i.d. dosing with CBTL or TXR. In this randomized, crossover study, 15 normal healthy adults received 400 mg of each formulation b.i.d. for 5 days. Blood samples for CBZ and CBZ-E analysis were obtained prior to morning doses on all days and hourly for 12 h after the Day 5 dose. There was a minimum interperiod washout of 9 days. For CBTL and TXR, the key CBZ pharmacokinetic measures of area under the curve of concentration versus time (AUC(0-tau)), maximum concentration (Cmax), and minimum concentration (Cmin) were bioequivalent. The ratio for CBTL-to-TXR was 98% (90% confidence intervals, 92-104%), 107% (96-118%), and 96% (89-104%), respectively. Similar ratios were also observed for CBZ-E: 102% (97-107%), 99% (92-107%), and 93% (83-109%), respectively. In conclusion, CBTL b.i.d. and TXR b.i.d. were bioequivalent in their pharmacokinetic parameters for CBZ and CBZ-E after 5 days of dosing.
Administration, Oral↗
Sheep oocyte activation after intracytoplasmic sperm injection (ICSI).
The effect of calcium concentration on fertilization and activation was examined in oocytes injected in vitro with sperm. Oocytes were subjected to sperm injection, to sham injection or remained uninjected, and were then cultured for 19 h in bicarbonate-buffered synthetic oviduct fluid (BSOF) without calcium, or containing either calcium chloride or calcium ionophore. There was no difference in fertilization rates after ICSI when oocytes were cultured in vitro in media containing calcium chloride or calcium ionophore but the rate was lower in calcium-free media. There was also no difference in the fertilization rate after ICSI when oocytes were cultured in vivo compared with that observed in vitro in media containing calcium chloride or calcium ionophore. In calcium chloride-treated oocytes, activation was induced by mechanical injection, and in calcium ionophore-treated oocytes, by the ionophore. In uninjected oocytes, calcium itself did not cause oocyte activation. It is concluded that it is possible to induce activation by the injection process, but that manipulation alone is inadequate to cause proper oocyte activation unless calcium is also present. No difference in oocyte activation between ICSI and sham injection was found, indicating that the sperm may play no role in the early events of oocyte activation.
Animals↗
The treatment of head injury during the Renaissance.
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Craniocerebral Trauma↗
Acute encephalopathy followed by permanent brain injury or death associated with further attenuated measles vaccines: a review of claims submitted to the National Vaccine Injury Compensation Program.
OBJECTIVE: To determine if there is evidence for a causal relationship between acute encephalopathy followed by permanent brain injury or death associated with the administration of further attenuated measles vaccines (Attenuvax or Lirugen, Hoechst Marion Roussel, Kansas City, MO), mumps vaccine (Mumpsvax, Merck and Co, Inc, West Point, PA), or rubella vaccines (Meruvax or Meruvax II, Merck and Co, Inc, West Point, PA), combined measles and rubella vaccine (M-R-Vax or M-R-Vax II, Merck and Co, Inc, West Point, PA), or combined measles, mumps, and rubella vaccine (M-M-R or M-M-R II, Merck and Co, Inc, West Point, PA), the lead author reviewed claims submitted to the National Vaccine Injury Compensation Program. METHODS: The medical records of children who met the inclusion criteria of receiving the first dose of these vaccines between 1970 and 1993 and who developed such an encephalopathy with no determined cause within 15 days were identified and analyzed. RESULTS: A total of 48 children, ages 10 to 49 months, met the inclusion criteria after receiving measles vaccine, alone or in combination. Eight children died, and the remainder had mental regression and retardation, chronic seizures, motor and sensory deficits, and movement disorders. The onset of neurologic signs or symptoms occurred with a nonrandom, statistically significant distribution of cases on days 8 and 9. No cases were identified after the administration of monovalent mumps or rubella vaccine. CONCLUSIONS: This clustering suggests that a causal relationship between measles vaccine and encephalopathy may exist as a rare complication of measles immunization.
Acute Disease↗
Risky business: challenges in vaccine risk communication.
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Attitude to Health↗
Report of a US public health service workshop on hypotonic-hyporesponsive episode (HHE) after pertussis immunization.
Hypotonic-hyporesponsive episode (HHE) is a term used to describe a somewhat heterogenous group of clinical disorders that have been reported primarily in association with whole-cell pertussis vaccination. A 1991 review by the Institute of Medicine determined that the evidence available was indeed consistent with a causal relation between whole-cell pertussis-diphtheria-tetanus immunization and HHE, but that the evidence was insufficient to indicate a causal relationship between HHE and the subsequent development of permanent neurologic damage. More recent data from clinical trials conducted in Europe suggest that HHE also occurs after vaccination with acellular pertussis vaccines. The US Food and Drug Administration, in collaboration with the US Public Health Service, sponsored a workshop on HHE in Rockville, Maryland, on June 19, 1997. The primary goals of the workshop were to develop a case definition of HHE and to evaluate the general design and feasibility of possible studies of HHE using the federal Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system. The goals of such studies would be to understand better the acute HHE event and to evaluate the possibility of long-term sequelae. Case Definition. There has been no generally accepted definition of HHE, and a standard definition would be useful for vaccine safety work and would potentially facilitate interstudy comparisons of the growing number of licensed vaccines containing acellular pertussis components. The workshop defined HHE as an event of sudden onset occurring within 48 hours of immunization, with duration of the episode ranging from 1 minute to 48 hours, in children younger than 10 years of age. All of the following must be present: 1) limpness or hypotonia, 2) reduced responsiveness or hyporesponsiveness, and 3) pallor or cyanosis or failure to observe or to recall skin coloration. HHE is not considered to have occurred if there is a known cause for these signs (eg, postictal), if urticaria is present during the event, if normal skin coloration is observed throughout the episode, or if the child is simply sleeping. This inclusive (sensitive) case definition will allow investigators, through the technique of stratification according to certain characteristics (eg, time from vaccination to onset of HHE), to attempt to hone the definition and make it more specific. Refinement of the definition of HHE has been hindered by the lack of information on its pathophysiology and by the lack of pathognomonic signs, symptoms, and diagnostic tests. Another hindrance is that by the time the child presents for medical evaluation, the signs of HHE often have normalized. Moreover, different mechanisms may be involved in different individuals whose events meet this workshop's HHE definition. Further Study of HHE. Probably the most important question about HHE is whether it has any permanent sequelae. The workshop assessed the possible contribution VAERS-based studies could make to answering this question and found substantial methodologic problems; however, ongoing studies in Sweden and The Netherlands have the potential to provide useful information on this question. The most useful contribution of VAERS data would be in a descriptive study of HHE, with a possible case-control study of factors that may affect the risk of HHE after vaccination, rather than a study of possible permanent sequelae. The workshop participants felt that a detailed descriptive study of approximately 100 HHE events reported during a 1- to 2-year period could provide a more in-depth description of HHE cases in greater numbers than has been published previously, but the study would not address the issue of long-term sequelae of HHE. Better descriptive data may lead to new hypotheses concerning risk factors, etiology, and pathophysiology of HHE that might be evaluated further by studying subsequent cases and controls from VAERS or from other sources, depending on the hypoth
Adverse Drug Reaction Reporting Systems↗
Effect of feed restriction and season on LH and prolactin secretion, adrenal response, insulin and FFA in group housed pregnant gilts.
A trial was designed to determine the effect of season and feed restriction on LH and prolactin secretion, adrenal response, insulin and FFA in the early pregnant gilt. Groups of cross bred gilts (n = 24) were mated and allocated to two feeding levels; a non-restricted group received close to ad libitum feeding of 3.6 kg whereas, the restricted group received 1.8 kg as recommended by the NRC. The trial was carried out in winter-spring and repeated in summer-autumn to investigate the effects of season. The feeding regimen were fed to the group housed animals for the first two weeks of pregnancy. A 12 h period of blood sampling every 15 min thereafter revealed higher amplitude LH pulses with larger area under the curve in winter compared with summer (1.17 +/- 0.03 vs. 0.69 +/- 0.03 ng ml(-1) and 65.09 +/- 1.46 vs. 33.60 +/- 1.25, P < 0.05). Overall, feed restriction reduced LH pulse frequency (2.5 +/- 0.1 and 1.6 +/- 0.1 pulses/12 h for high and low feeding levels, P < 0.05), but the difference was large in winter and no difference was detected in summer. An ACTH challenge test carried out the day after the frequent sampling revealed greater response to the ACTH challenge in winter in comparison with summer. Plasma prolactin values were generally very low and ranged from 1 to 4.5 ng/ml with highest values detected in the feed restricted group in summer. Plasma FFA and insulin concentrations showed greater pre- versus post-prandial variation in the feed restricted groups. It was concluded, that feed restriction and season affected LH secretion and those effects appeared to be related to the metabolic changes in the early pregnant group housed gilt.
Adrenal Glands↗
Altered secretion of LH does not explain seasonal effects on early pregnancy in gilts.
This work was undertaken to study the effects of energy intake and gut fill on LH secretion in the early pregnant gilt to investigate the role of the hypothalamo-pituitary-gonadal axis in the seasonal disruption of pregnancy. Four groups of mated gilts (N = 23 in total) were individually housed and fed four different energy levels (23, 46, 47 and 55 megajoules digestible energy per day, MJ DE day-1) for two weeks after mating during the season identified as a period of increased rate of early pregnancy failures from January till April (summer-autumn). The energy content of base feed (13 MJ kg-1) was increased by means of adding a fat supplement (soybean oil) to the feed of two groups of gilts, while the other two groups were given different levels of the basic feed. The groups gained weight and backfat according to energy intake levels during the two-week period. Frequent blood samples (15-min interval) collected on day 14 revealed a significant treatment effect on LH pulse amplitude: the group on the highest energy intake level (55 MJ DE day-1) had higher LH pulse amplitude compared with the other groups (1.01 +/- 0.04, 0.74 +/- 0.04, 0.72 +/- 0.08 and 0.66 +/- 0.05 ng ml-1 in the descending order of energy intake, P < 0.01). There was no effect of energy intake on LH pulse frequency, mean level, area under the curve or mean nadir (P > 0.10). Plasma insulin concentrations tended to increase (P < 0.08) in each group with time after feeding, but no significant differences between the treatment groups were found. Plasma free fatty acid (FFA) concentrations were decreased 1 h after feeding (P < 0.05) in all but the group on 55 MJ DE day-1. This group also had higher postprandial FFA concentrations in comparison with other groups (P < 0.05). In conclusion, these results show that energy density of feed and energy intake have little effect on LH secretion in the early pregnant gilt. Protective effect of high feeding level against seasonal disruption of pregnancy appears to be mediated by mechanisms other than an alteration in LH secretion.
Animals↗
Functional characterization of human nucleosome assembly protein-2 (NAP1L4) suggests a role as a histone chaperone.
Histones are thought to play a key role in regulating gene expression at the level of DNA packaging. Recent evidence suggests that transcriptional activation requires competition of transcription factors with histones for binding to regulatory regions and that there may be several mechanisms by which this is achieved. We have characterized a human nucleosome assembly protein, NAP-2, previously identified by positional cloning at 11p15.5, a region implicated in several disease processes including Wilms tumor (WT) etiology. The deduced amino acid sequence of NAP-2 indicates that it encodes a protein with a potential nuclear localization motif and two clusters of highly acidic residues. Functional analysis of recombinant NAP-2 protein purified from Escherichia coli demonstrates that this protein can interact with both core and linker histones. We demonstrate that recombinant NAP-2 can transfer histones onto naked DNA templates. Deletion mutagenesis of NAP-2 demonstrates that both NH3- and COOH-terminal domains are required for histone transfer activity. Subcellular localization studies of NAP-2 indicate that it can shuttle between the cytoplasm and the nucleus, suggesting a role as a histone chaperone. Given the potential role of the human NAP-2 gene (HGMW-approved symbol NAP1L4) in WT etiology, we have elucidated the exon/intron structure of this gene and have analyzed the mutational status of NAP-2 in sporadic WTs. Our results, coupled with tumor suppression assays in G401 WT cells, do not support a role for NAP-2 in the etiology of WT. A putative role for NAP-2 in regulating cellular differentiation is discussed.
Amino Acid Sequence↗
A 1-Mb physical map and PAC contig of the imprinted domain in 11p15.5 that contains TAPA1 and the BWSCR1/WT2 region.
We have constructed a 1-Mb contig in human chromosomal band 11p15.5, a region implicated in the etiology of several embryonal tumors, including Wilms tumor, and in Beckwith-Wiedemann syndrome. Cosmid, P1, PAC, and BAC clones were characterized by NotI/SalI digestion and hybridized to a variety of probes to generate a detailed physical map that extends from D11S517 to L23MRP. Included in the map are the CARS, NAP2, p57/KIP2, KVLQT1, ASCL2, TH, INS, IGF2, H19, and L23MRP genes as well as end probes isolated from PACs. The TAPA1 gene, whose protein product can transmit an antiproliferative signal, was also localized in the contig. However, Northern blot analysis demonstrated that its expression did not correlate with tumorigenicity in G401 Wilms tumor hybrids, suggesting that TAPA1 is not responsible for the tumor suppression associated with 11p15.5. Genomic clones were used as probes in FISH analysis to map the breakpoints from three Beckwith-Wiedemann syndrome patients and a rhabdoid tumor. Interestingly, each of the breakpoints disrupts the KVLQT1 gene, which is spread over a 400-kb region of the contig. Since 11p15.5 contains several genes with imprinted expression and one or more tumor suppressor genes, our contig and map provide a framework for characterizing this intriguing genetic environment.
Antigens, CD↗
Stress fractures in a hyperactive 3-year-old girl.
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Child, Preschool↗
Organization and regulatory aspects of the human intestinal mucin gene (MUC2) locus.
The human MUC2 gene maps to chromosome 11p15, where three additional mucin genes have been located, and encodes the most abundant gastrointestinal mucin normally expressed in the intestinal goblet cell lineage. However, in pathological conditions, including colorectal cancer, MUC2 can be abnormally expressed. Therefore, it is of considerable interest to understand the regulation of the MUC2 gene and how the mechanism is altered in colon cancer. Toward this goal, we have isolated a group of overlapping clones (contig) spanning 85 kilobases harboring the entire MUC2 locus, including sequences located upstream of the gene. Detection of two DNase I-hypersensitive sites in the 5' region of the MUC2 gene suggests the presence of DNA regulatory elements. To better characterize this region, we have sequenced 12 kilobases of the upstream region and analyzed it for functional activity by cloning portions of it into a luciferase reporter vector and assaying for promoter/enhancer activity using a transient transfection assay. A fragment from the AUG translational initiation codon +1 to -848 confers maximal transcriptional activity in several intestinal cell lines. Elements located further upstream exert a negative effect on the expression of the reporter gene when tested in conjunction with homologous or heterologous promoters. The same pattern of expression is observed when the MUC2/luciferase constructs are transfected into HeLa cells, which do not express the endogenous MUC2 gene. However, the level of activity in HeLa cells is at least an order of magnitude higher, suggesting that additional sequences singularly or in combination are responsible for the tissue- and cell lineage-specific expression of MUC2. Finally, we have identified an additional mucin-like gene (MUCX), located upstream of MUC2. We show that this MUCX gene, that is transcribed in opposite orientation to that of MUC2, is expressed with a pattern distinct from that of MUC2, yet similar to that of MUC5B and MUC6, two additional mucin genes located at chromosome 11p15. Recent information on the order of the mucin genes at chromosome 11p15 suggests that MUCX may be MUC6, one of the already identified mucin genes, or a novel one, yet to be fully characterized.
Amino Acid Sequence↗
In vitro and in vivo developmental capacity of oocytes from prepubertal and adult sheep.
Development to the blastocyst stage and survival following embryo transfer were assessed for oocytes obtained from prepubertal and adult sheep matured and fertilized in vitro. The rates of maturation, fertilization and cleavage in vitro did not differ significantly between oocytes from prepubertal and adult sheep. The proportion of cleaved zygotes reaching the blastocyst stage was significantly lower for oocytes derived from prepubertal than for those from adult sheep (15.4% and 34.1% respectively). There were no differences in the pregnancy rate and number of lambs born following transfer of blastocyst stage embryos derived from prepubertal and adult sheep to adult recipients. These data show that embryos derived from prepubertal lamb oocytes have reduced developmental potential in vitro but, of those which do reach the blastocyst stage, they have equal capacity to develop to term as embryos derived from adult sheep.
Journal Article↗