Biomedical subjects
N Cox
Publications and source records attributed to N Cox.
Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness.
An avian H5N1 influenza A virus (A/Hong Kong/156/97) was isolated from a tracheal aspirate obtained from a 3-year-old child in Hong Kong with a fatal illness consistent with influenza. Serologic analysis indicated the presence of an H5 hemagglutinin. All eight RNA segments were derived from an avian influenza A virus. The hemagglutinin contained multiple basic amino acids adjacent to the cleavage site, a feature characteristic of highly pathogenic avian influenza A viruses. The virus caused 87.5 to 100 percent mortality in experimentally inoculated White Plymouth Rock and White Leghorn chickens. These results may have implications for global influenza surveillance and planning for pandemic influenza.
Impact of epidemic influenza A-like acute respiratory illness in a remote jungle highland population in Irian Jaya, Indonesia.
A suspected epidemic of unknown etiology was investigated in April/May 1996 in the remote jungle highlands of easternmost Indonesia. Trend analysis demonstrates the area-wide occurrence of a major respiratory infection outbreak in November 1995 through February 1996. The monthly mean rate of respiratory infection episodes for the peak outbreak months (2,477 episodes/100,000 persons) was significantly higher (P < .0001) than for the 34 months leading up to the outbreak (109 episodes/100,000 persons). Notable were the high attack rates, particularly among adults: 202 episodes/1,000 persons aged 20-50 years in one community. Excess morbidity attributed to the outbreak was an estimated 4,338 episodes. The overall case-fatality rate was 15.1% of outbreak cases. Laboratory evidence confirmed the circulation of influenza A/Taiwan/1/86-like viruses in the study population, and high hemagglutination inhibition titer responses were indicative of recent infections. Historical documents from neighboring Papua New Guinea highlight the role of influenza A virus in repeated area outbreaks.
Comparisons of highly virulent H5N1 influenza A viruses isolated from humans and chickens from Hong Kong.
Genes of an influenza A (H5N1) virus from a human in Hong Kong isolated in May 1997 were sequenced and found to be all avian-like (K. Subbarao et al., Science 279:393-395, 1998). Gene sequences of this human isolate were compared to those of a highly pathogenic chicken H5N1 influenza virus isolated from Hong Kong in April 1997. Sequence comparisons of all eight RNA segments from the two viruses show greater than 99% sequence identity between them. However, neither isolate's gene sequence was closely (>95% sequence identity) related to any other gene sequences found in the GenBank database. Phylogenetic analysis demonstrated that the nucleotide sequences of at least four of the eight RNA segments clustered with Eurasian origin avian influenza viruses. The hemagglutinin gene phylogenetic analysis also included the sequences from an additional three human and two chicken H5N1 virus isolates from Hong Kong, and the isolates separated into two closely related groups. However, no single amino acid change separated the chicken origin and human origin isolates, but they all contained multiple basic amino acids at the hemagglutinin cleavage site, which is associated with a highly pathogenic phenotype in poultry. In experimental intravenous inoculation studies with chickens, all seven viruses were highly pathogenic, killing most birds within 24 h. All infected chickens had virtually identical pathologic lesions, including moderate to severe diffuse edema and interstitial pneumonitis. Viral nucleoprotein was most frequently demonstrated in vascular endothelium, macrophages, heterophils, and cardiac myocytes. Asphyxiation from pulmonary edema and generalized cardiovascular collapse were the most likely pathogenic mechanisms responsible for illness and death. In summary, a small number of changes in hemagglutinin gene sequences defined two closely related subgroups, with both subgroups having human and chicken members, among the seven viruses examined from Hong Kong, and all seven viruses were highly pathogenic in chickens and caused similar lesions in experimental inoculations.
HLA and mate choice in humans.
Evidence from studies in rodents suggests that mate selection is influenced by major-histocompatibility-complex haplotypes, with preferences for dissimilar partners. This study was initiated to determine whether avoidance of a mate with the same HLA haplotype as one's own might be occurring in the Hutterites, a North American reproductive isolate of European ancestry, notable for their large sibships, communal lifestyle, and limited number of five-locus HLA haplotypes (HLA-A, -B, -C, -DR, and -DQ). HLA haplotypes were known for 411 Hutterite couples. The number of couples expected to match for a haplotype was calculated in two ways: first, from population genotype frequencies, with account being taken of the nonrandom mating pattern with respect to colony lineages, and, second, from computer simulations using conservative founder assumptions and the exact genealogy of the 411 couples. We observed fewer matches for HLA haplotypes between spouses than expected (first method, P = .005; second method, P = .020-.067). Among couples who did match for a haplotype, the matched haplotype was inherited from the mother in 29 cases and from the father in 50 cases (P = .018). These results are consistent with the conclusion that Hutterite mate choice is influenced by HLA haplotypes, with an avoidance of spouses with haplotypes that are the same as one's own.
Pulmonary lymphangioleiomyomatosis and cerebrotendinous xanthomatosis: is there a link?
A 41-year-old woman had progressive shortness of breath. Cerebrotendinous xanthomatosis was diagnosed 4 years before. An open-lung biopsy showed the simultaneous presence of cerebrotendinous xanthomatosis and pulmonary lymphangioleiomyomatosis. This is perhaps the first time the coincidental occurrence of these two diseases is described.
Kinetics of humoral response in children with acute lymphoblastic leukemia immunized with influenza vaccine in 1993 in Poland.
A total of 49 children with acute lymphoblastic leukemia were immunized with a purified subvirion trivalent influenza vaccine (Wyeth-USA) and monitored for hemagglutination inhibition (HI) and neuraminidase inhibition (NI) antibodies before vaccination, and then three weeks and six months after vaccination. Results for HI antibodies were evaluated as geometric mean titre (GMT), mean fold antibody increase (MFI), protection and response rates and those for NI antibodies as geometric mean titre (GMT) and mean fold antibody increase (MFI). Six months after vaccination GMT for hemagglutinin 1 (H1) was much higher than previous values. GMT for hemagglutinin 3 (H3) and hemagglutinin B (HB) was lower than three weeks after vaccination, but much higher than the original values. In the control group GMT for H1 was on a low level all the time and for H3 and HB it was lower when compared with the original values. The proportion of vaccines to antibodies > or = 40 ranged between 45% and 88%. Six months after vaccination GMT for neuraminidase 1 (N1) increased when compared with the second sampling; for neuraminidase 2 (N2) and neuraminidase B (NB) it was slightly lower. In the control group GMT for all antigens was on a low level all the time. The results point to a significant seroconversion for both components after vaccination when compared with the control group.
Genetics of stuttering: a critical review.
The fact that stuttering runs in families has been documented over a long period and has led to speculations and research about the role of a genetic component to this disorder. Although the genetic factor cannot be proved by familial aggregation and twin studies alone, such research has continued to provide support for a relationship between stuttering and genetics. The purposes of this article are to review and critique the research in this area. The article first assesses research methodologies that have been employed in familial studies of stuttering. It proceeds to review and critique incidence, twin, and aggregation studies. In addition, it includes sections on subgroups, genetic models of stuttering, and implications for future research as well as for clinical work. With a focus on improved methodology and recent findings, a current perspective on our knowledge of the genetic component to stuttering is provided. Among other conclusions, the article emphasizes that failure to consider epidemiologic factors has probably biased previous results regarding the genetics of stuttering. New preliminary data also appear to provide evidence that spontaneous recovery and chronicity are influenced by genetic factors. Generally, however, the review of incidence and twin studies, as well as of evidence for the various inheritance models, confirms previous conclusions about the interaction between genetic and environmental factors in stuttering.
The gene responsible for autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) maps to chromosome 2p16.
Degeneration in the macula region of the retina is a feature of a heterogeneous group of inherited, progressive disorders, causing blinding visual impairment. Autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) is characterised by the presence of drusen deposits at the level of Bruch's membrane in the macula and around the edge of the optic nerve head. We have studied 63 members of a large, nine-generation British pedigree by linkage analysis. Two-point analysis showed significant linkage to nine markers on the short arm of chromosome 2, a region overlapping that recently reported to be linked to Malattia leventinese. A maximum lod score (Zmax) of 7.29 (theta = 0.0) was obtained at marker locus D2S2251. Haplotype analysis of recombination events localised the disease to a 5 cM region between marker loci D2S2316 and D2S378. Striking clinical similarities between DHRD and the more common condition age-related macular degeneration (ARMD) suggest that the disease gene at this locus could be considered as the most likely candidate in future studies on ARMD.
Comparison of US inactivated split-virus and Russian live attenuated, cold-adapted trivalent influenza vaccines in Russian schoolchildren.
In a blinded, placebo-controlled study, the reactogenicity, immunogenicity, and clinical efficacy of single doses of US inactivated split-virus and Russian live attenuated, cold-adapted influenza vaccines were compared in 555 schoolchildren in Vologda, Russia. Serial serum samples were collected and school absenteeism was assessed. Systemic reactions were rare, but local reactions (primarily erythema at the injection site) were observed in 27% of the inactivated vaccine group, and coryza (12%) and sore throat (8%) were observed in the attenuated vaccine group. At 4 weeks after vaccination a > or = 4-fold rise in titer of hemagglutination inhibition antibody to A (H1N1), A (H3N2), and B was noted, respectively, among 78%, 88%, and 53% of children who received inactivated vaccine and among 55%, 79%, and 30% of children who received attenuated vaccine. The vaccine efficacy for preventing school absenteeism due to respiratory illness during the period of peak influenza activity was 56% for inactivated vaccine and 47% for attenuated vaccine.
[Vaccination against influenza in children with acute lymphoblastic leukemia].
In November and December 1993, 49 children, ages 4 to 20, suffering from acute lymphoblastic leukemia, were vaccinated against influenza in the Department of Paediatric Haematology and Oncology, Medical Academy in Warsaw. These patients were vaccinated either in the course of maintenance treatment or after treatment. Each dose of Wyeth USA subunit trivalent influenza vaccine contained 15 micrograms of hemagglutinin of strains recommended for that season. The level of antibody production was determined in pre- and post vaccination sera in the group of children with leukemia and the control group. It was determined that in the investigated group, the GMT increased more than four times for hemagglutinins H1N1 and H3N2. A somewhat lower increase was observed in case of hemagglutinin HB. The proportion of subjects protected after vaccination was 35% for hemagglutinin H1N1, 76% for H3N2 and 100% for HB. The response rate was 33% for hemagglutinin H1N1, 47% for H3N2 and 45% for HB. In the control group the proportion of subjects protected and the response rate were very low. The results show the significant immunological efficacy of the vaccine used in the vaccination against influenza in high risk groups.
Amantadine-resistant influenza A in nursing homes. Identification of a resistant virus prior to drug use.
BACKGROUND: Amantadine hydrochloride and rimantadine hydrochloride have been used for treatment and prevention of influenza A infection in nursing home residents. Outbreaks of influenza A (H3N2) virus infection occurred in three nursing homes in Yakima County, Washington, during January 1992. Amantadine was used for case treatment and prophylaxis in all three nursing homes. METHODS: Ten influenza A (H3N2) viruses isolated during the outbreaks were examined for resistance to amantadine and rimantadine by means of an enzyme immunoassay and by sequencing of the viral nucleic acid that encodes the transmembrane domain of the M2 protein. RESULTS: Five of the outbreak strains were resistant and had the same mutation (position 31, serine to asparagine) in the M2 protein. The resistant viruses included one that had been recovered prior to any use of amantadine and another that was recovered within 48 hours of the first drug administration. CONCLUSIONS: To our knowledge, this is the first report of influenza A virus with RNA sequence-documented resistance to amantadine and rimantadine without exposure to either drug, and the shortest reported period between institution of amantadine therapy and isolation of a resistant influenza A virus strain. These results suggest that surveillance for amantadine- and rimantadine-resistant influenza A is needed, because use of these drugs will probably increase.
Outcome in patients who require a gastrostomy after stroke.
Dysphagia is common after a stroke and is associated with a poor outcome in terms of survival or functional recovery. Percutaneous gastrostomy (PG) provides reliable and safe nutrition for patients with neurological dysphagia in the short term but little is known about the the subsequent outcome in stroke patients. We reviewed the medical records of all stroke patients who had required a PG in four West Yorkshire hospitals over a 30-month period. All patients alive at the time of the study were contacted and functional status was recorded. Forty-one stroke patients had undergone PG and 37 records were obtained. There were 24 men and 13 women with a mean age of 74 years. Thirty-three patients had had a hemiplegia while four patients presented acutely with dysphagia but no hemiplegia (all had cerebral infarcts on CT scan). The timing of PG varied with a median time from stroke of 26 days (range 12-131). Complications include five chest infections ( < 1 week after PG), three local infections, two tubes pulled out and one perforation. Three patients died in the first 5 days after the PG. Thirty-one of the 37 patients had died at the time of the assessment, 21 during the original hospital admission. The median survival from the time of PG was 53 days (range 2-528) with only 12 patients surviving for more than 3 months. Six patients were alive at the time of the study and all but one were severely disabled (mean modified Barthel Index seven). There is no consensus about patients selection or timing of PG and our data should lead to more careful consideration of the risks and benefits of the procedure in stroke patients.
Linkage of familial dysalbuminemic hyperthyroxinemia to the albumin gene in a large Amish kindred.
Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasians. Transmitted as an autosomal dominant trait, it is always associated with high serum total T4 (TT4) and more rarely with elevated total T3 (TT3) and/or rT3 (TrT3) concentrations. Free T4, by dialysis, and TSH levels are normal, suggesting the presence of a T4-binding protein abnormality. The abnormal serum T4 carrier shares some physical and immunological properties with albumin, suggesting that it may be albumin itself. Here we show linkage between FDH and the albumin gene in a large Amish family of Swiss descent, using as markers a SacI polymorphism in the coding sequence of the albumin gene and the group-specific component (Gc) gene, located less than 1 centimorgan from the albumin gene. Blood samples were obtained from 160 members of this kindred, and 22 had FDH identified by the pattern of T4 binding to serum proteins separated by isoelectric focusing. Serum TT4 values were above the normal range in all subjects expressing the FDH phenotype, and TrT3 levels were above the normal range in only one half. TT4 concentrations correlated positively with TrT3 and TT3. All TT3 values were, however, within the normal range. Free T4 and TSH levels were normal, confirming the euthyroid state in these subjects. FDH was associated with the albumin SacI(+)/Gc 1S haplotype, yielding a LOD (logarithm of the odds ratio) score of 5.53, with a recombination frequency of 0. These data provide strong support that a variant albumin is the cause of FDH in this kindred.
[Influenza vaccination of children with hemophilia].
51 haemophilic children aged from 7 to 16 years was vaccinated against influenza in Paediatric Department of Haematology and Oncology in November and December of 1993. Each dose of subunit vaccine manufactured by Wyeth-USA, contained 15 micrograms of each haemagglutinin strains as recommended for the season. The antibody level was studied before and after influenza vaccination in vaccinated and control group as well. 5-time rise of geometric mean antibody titre was found for H1N1 and H3N2 antigens after vaccination of the children group. Slightly lower, 2.7-time rise of GMT was showed for HB haemagglutinin of influenza virus. There was no significant rise of GMT for any among three studied virus haemagglutinin.
Sequential imputation for multilocus linkage analysis.
A Monte Carlo method called sequential imputation is proposed for multilocus likelihood computations. This method is most useful in mapping situations where the data consist of large pedigrees with substantial missing information and it is desirable to perform linkage analysis utilizing data from many polymorphic markers simultaneously. A pedigree example with 155 individuals, 9 loci, and 155,520 haplotypes is used for illustration.
Sequential imputation and multipoint linkage analysis.
A novel Monte Carlo method for linkage analyses involving large pedigrees and many polymorphic loci is introduced. Issues related to the efficiency of the method are discussed.
Genetic aspects of early childhood stuttering.
Although stuttering has long been acknowledged as a familial disorder, the nature of a genetic component remains unclear. Most previous data used in genetic studies were obtained primarily from adults who stutter and may be biased in several respects. The purpose of this investigation was to quantify the frequency of stuttering in relatives of preschool-age children who stutter, and who were first seen close to the onset of the disorder. Detailed pedigrees (family trees), including first-, second-, and third-degree relatives, were obtained from parents of 69 children who stuttered. We found, as have previous studies, that more male than female relatives ever stuttered, but that female subjects who stuttered had more female relatives who ever stuttered than did male subjects. In order to identify the genetic model most consistent with the observed patterns of stuttering transmission, we conducted segregation analyses. Results from these analyses suggest that transmission of a single major genetic locus increasing the liability to stuttering best accounts for the transmission of stuttering in families of preschool-age children who stutter.