A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer.
The frequency, origin, and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated. The mutation (A-->T at nt943+3) disrupts the 3' splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported. Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England, more extensive analysis has reduced the frequency to four of 52 (8%) English HNPCC kindreds analysed. In contrast, the MSH2 mutation was identified in 10 of 20 (50%) separately identified colorectal families from Newfoundland. To investigate the origin of this mutation in colorectal cancer families from England (n=4), Newfoundland (n=10), and the United States (n=3), haplotype analysis using microsatellite markers linked to MSH2 was performed. Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families. In contrast, a common haplotype was identified at the two flanking markers (CA5 and D2S288) in eight of the Newfoundland families. These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families. We calculated age related risks of all, colorectal, endometrial, and ovarian cancers in nt943+3 A-->T MSH2 mutation carriers (n=76) for all patients and for men and women separately. For both sexes combined, the penetrances at age 60 years for all cancers and for colorectal cancer were 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (p<0.01) in males than females (0.63 v 0.30 and 0.84 v 0.44 at ages 50 and 60 years, respectively). For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers. (+info)
North American and European porcine reproductive and respiratory syndrome viruses differ in non-structural protein coding regions.
Although North American and European serotypes of porcine reproductive and respiratory syndrome virus (PRRSV) are recognized, only the genome of the European Lelystad strain (LV) has been sequenced completely. Here, the genome of the pathogenic North American PRRSV isolate 16244B has been sequenced and compared with LV. The genomic organization of 16244B was the same as LV but with only 63.4% nucleotide identity. The 189 nucleotide 5' non-coding region (NCR) of 16244B was distinct from the LV NCR, with good conservation (83%) only over a 43 base region immediately upstream of open reading frame (ORF) 1a. Major differences were found in the region encoding the non-structural part of the ORF1a polyprotein, which shared only 47% amino acid identity over 2503 residues of the six non-structural proteins (Nsps) encoded. Nsp2, thought to have a species-specific function, showed the greatest divergence, sharing only 32% amino acid identity with LV and containing 120 additional amino acids in the central region. Nsps encoded by the 5'-proximal and central regions of ORF1b had from 66 to 75% amino acid identity; however, the carboxy-terminal protein CP4 was distinct (42% identity). The ORF 1a-1b frameshift region of 16244B had 98% nucleotide identity with LV. Consistent with previous reports for North American isolates, the six structural proteins encoded were 58 to 79% identical to LV proteins. The 3' NCR (150 nucleotides) was 76% identical between isolates. These genomic differences confirm the presence of distinct North American and European PRRSV genotypes. (+info)
Comparison of European and North American malignant hyperthermia diagnostic protocol outcomes for use in genetic studies.
BACKGROUND: Halothane and caffeine diagnostic protocols and an experimental ryanodine test from the North American Malignant Hyperthermia (MH) Group (NAMHG) and the European MH Group (EMHG) have not been compared in the same persons until now. METHODS: The outcomes of the NAMHG and EMHG halothane and caffeine contracture tests were compared in 84 persons referred for diagnostic testing. In addition, the authors assessed the experimental ryanodine protocol in 50 of these persons. RESULTS: Although the NAMHG and EMHG halothane protocols are slightly different methodologically, each yielded outcomes in close (84-100%) agreement with diagnoses made by the other protocol. Excluding 23 persons judged to be equivocal (marginally positive responders) by the EMHG protocol resulted in fewer persons classified as normal and MH susceptible (42 and 19, respectively) than those classified by the NAMHG protocol (48 and 34, respectively). For the 61 persons not excluded as equivocal, the diagnoses were identical by both protocols, with the exception of one person who was diagnosed as MH susceptible by the NAMHG protocol and as "normal" by the EMHG protocol. The NAMHG protocol produced only two equivocal diagnoses. Therefore, a normal or MH diagnosis by the NAMHG protocol was frequently associated with an equivocal diagnosis by the EMHG protocol. The time to 0.2-g contracture after the addition of 1 microM ryanodine completely separated populations, which was in agreement with the EMHG protocol and, except for one person, with the NAMHG protocol. CONCLUSIONS: Overall, the NAMHG and EMHG protocols and the experimental ryanodine test yielded similar diagnoses. The EMHG protocol reduced the number of marginal responders in the final analysis, which may make the remaining diagnoses slightly more accurate for use in genetic studies. (+info)
Genetic diversity and distribution of Peromyscus-borne hantaviruses in North America.
The 1993 outbreak of hantavirus pulmonary syndrome (HPS) in the southwestern United States was associated with Sin Nombre virus, a rodent-borne hantavirus; The virus' primary reservoir is the deer mouse (Peromyscus maniculatus). Hantavirus-infected rodents were identified in various regions of North America. An extensive nucleotide sequence database of an 139 bp fragment amplified from virus M genomic segments was generated. Phylogenetic analysis confirmed that SNV-like hantaviruses are widely distributed in Peromyscus species rodents throughout North America. Classic SNV is the major cause of HPS in North America, but other Peromyscine-borne hantaviruses, e.g., New York and Monongahela viruses, are also associated with HPS cases. Although genetically diverse, SNV-like viruses have slowly coevolved with their rodent hosts. We show that the genetic relationships of hantaviruses in the Americas are complex, most likely as a result of the rapid radiation and speciation of New World sigmodontine rodents and occasional virus-host switching events. (+info)
Genetic diversity of equine arteritis virus.
Equine arteritis viruses (EAV) from Europe and America were compared by phylogenetic analysis of 43 isolates obtained over four decades. An additional 22 virus sequences were retrieved from GenBank. Fragments of the glycoprotein G(L) and the replicase genes were amplified by RT-PCR, prior to sequencing and construction of phylogenetic trees. The trees revealed many distinctive lineages, consistent with prolonged diversification within geographically separated host populations. Two large groups and five subgroups were distinguished. Group I consisted mainly of viruses from North America, whilst group II consisted mainly of European isolates. In most instances, where the geographic origin of the viruses appeared to be at variance with the phylogenetically predicted relationships, the horses from which the viruses were recovered had been transported between Europe and America or vice versa. Analysis of the replicase gene revealed similar phylogenetic relationships although not all of the groups were as clearly defined. Virus strains CH1 (Switzerland, 1964) and S1 (Sweden, 1989) represented separate 'outgroups' based on analysis of both genomic regions. The results of this study confirm the value of the G(L) gene of EAV for estimating virus genetic diversity and as a useful tool for tracing routes by which EAV is spread. In addition, computer-assisted predictions of antigenic sites on the G(L) protein revealed considerable variability among the isolates, especially with respect to regions associated with neutralization domains. (+info)
Containing health costs in the Americas.
In recent years, a series of policy measures affecting both demand and supply components of health care have been adopted in different Latin American and Caribbean countries, as well as in Canada and the United States. In applying these measures various objectives have been pursued, among them: to mobilize additional resources to increase operating budgets; to reduce unnecessary utilization of health services and consumption of pharmaceuticals; to control increasing production costs; and to contain the escalation of health care expenditures. In terms of demand management, some countries have established cost-recovery programmes in an attempt to offset declining revenues. These measures have the potential to generate additional operating income in public facilities, particularly if charges are levied on hospital care. However, only scant information is available on the effects of user charges on demand, utilization, or unit costs. In terms of supply management, corrective measures have concentrated on limiting the quantity and the relative prices of different inputs and outputs. Hiring freezes, salary caps, limitations on new construction and equipment, use of drug lists, bulk procurement of medicines and vaccines, and budget ceilings are among the measures utilized to control production costs in the health sector. To moderate health care expenditures, various approaches have been followed to subject providers to 'financial discipline'. Among them, new reimbursement modalities such as prospective payment systems offer an array of incentives to modify medical practice. Cost-containment efforts have also spawned innovations in the organization and delivery of health services. Group plans have been established on the basis of prepaid premiums to provide directly much or all health care needs of affiliates and their families. The issue of intrasectorial co-ordination, particularly between ministries of health and social security institutions, has much relevance for cost containment. In various countries, large-scale reorganization processes have been undertaken to eliminate costly duplications of resources, personnel, and services that resulted from the multiplicity of providers in the public subsector. Given the pluralistic character of the region's health systems, an important challenge for policy-makers is to find ways to redefine the role of state intervention in health from the simple provision of services to one that involves the 'management' of health care in the entire sector. (+info)
The prevalence of low back pain in adults: a methodological review of the literature.
The prevalence of low back pain (LBP) has been reported in the literature for different populations. Methodological differences among studies and lack of methodological rigor have made it difficult to draw conclusions from these studies. A systematic review was done for adult community prevalence studies of LBP published from 1981 to 1998. The technique of capture-recapture was performed to estimate the completeness of the search strategy used. Established guidelines and a methodological scoring system were used to critically appraise the studies. Thirteen studies were deemed methodologically acceptable. Differences in the duration of LBP used in the studies appeared to affect the prevalence rates reported and explain much of the variation seen. It was estimated that the point prevalence rate in North America is 5.6%. Further studies using superior methods are needed, however, before this estimate can be used with confidence to make health care policies and decisions relating to physical therapy. (+info)
Lymphatic and hematopoietic cancer in teachers.
A recent study found high rates of leukemia and related disorders among teachers. This finding may be related to exposure to childhood infections. Therefore, epidemiologic studies on the risk of lymphatic and hematopoietic cancer among teachers were systematically reviewed. Altogether 26 relevant investigations were identified, most from ad hoc publications rather than from scientific journals. Elevated risks of leukemia, lymphoma, and multiple myeloma were found in studies using proportional mortality or mortality odds ratios as outcome measures. However, these observations may reflect low overall mortality and do not necessarily indicate high death rates from the cancers of interest. In studies deriving standardized mortality or incidence ratios, the risk estimates were generally lower. The most striking finding was for non-Hodgkin's lymphoma (approximate summary relative risk 1.36, 95% confidence interval 1.13-1.62), but it was likely to have been exaggerated by publication bias. In conclusion, no compelling epidemiologic evidence exists for a hazard of leukemia or related diseases among teachers. (+info)