Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis.

Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing-remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P < 10(-4), chi(2)). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One interleukin 7 receptor (IL7R) promoter single nucleotide polymorphism (SNP), -504 C, was undertransmitted in PPMS trios (P = 0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P = 0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P < 0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.

Gestational diabetes. Incidence, maternal characteristics, and perinatal outcome.

Accurate estimates of the incidence of abnormal glucose tolerance during pregnancy are virtually nonexistent. Screening select populations of women with risk factors for the condition and the nonrandom, non-population-based nature of most studies have given rise to wide variances in reported incidence. We analyzed data from the states of Mississippi and Washington and from the National Natality and Fetal Mortality Surveys conducted in 1980 in an attempt to provide more accurate population-based estimates of the incidence of gestational diabetes mellitus (GDM). In the national surveys GDM was noted (screening and diagnostic criteria were unavailable) as a complication in 0.38% of all sampled pregnancies; overt (type I and type II) diabetes was noted in 0.78%. Mean maternal age for the GDM group was 28.4 yr; 85% were white (81% controls) and 15% non-white (19% controls). Prepregnancy weights were higher in the GDM group by an average of 20 lb. However, mean weight gain was less in this group than in controls (23 versus 29 lb). Perinatal mortality was noted in approximately 2.8% (1.3% in controls) of the offspring in GDM-complicated pregnancies and congenital malformations in 6.4% (7.9% in controls). Methodologic problems were encountered and included lack of screening and diagnostic criteria, underreporting, and underrecording.

Surveillance of acute complications of new therapies.

In its essence, surveillance is the continuous gathering, analysis, and dissemination of data to those who need to know for the purposes of disease control. To understand the complications of new therapies, data concerning the type and number of complications (numerator) and the population at risk for complications (denominator) must be gathered. Information about the expected rates of complications among comparison populations must be known to place the observed rates into perspective. Such data may be developed through active or passive reporting systems, clinic-based surveillance, follow-up of sentinel events, and registries. An investigation of mortality among users of continuous subcutaneous insulin infusion (CSII) pumps is used as an example.

An approach to the prevention of blindness in diabetes.

Diabetic eye disease is the leading cause of new cases of legal blindness in American adults under the age of 65 yr. Diabetic persons are at risk for visual loss due to diabetic retinopathy, glaucoma, and cataracts. Better understanding of the natural histories of these complications and recent advances in treatment have provided a rationale for developing an approach to prevent visual loss. This approach requires that diabetic patients who are at high risk for visual loss, and not under the care of ophthalmologists, be systematically screened, referred, and treated.

An epidemiologic model for diabetes mellitus: incidence, prevalence, and mortality.

An epidemiologic model is developed to describe the incidence, prevalence, and mortality of diabetes. Available data are reviewed, analyzed, and applied to the model. The model provides a framework for understanding diabetes on a population basis, and is useful in identifying needs and facilitating health care planning.

TAP2 polymorphisms in Australian multiple sclerosis patients.

Polymorphism of the TAP2 gene locus, situated approximately 150 kb centromeric to the MHC class II loci HLA-DR, DQ was examined in 100 Australian patients with relapsing/remitting multiple sclerosis (MS), in 100 random controls and in 37 selected HLA-DRB1*1501-positive controls. The results were correlated with HLA class I and class II phenotypes. TAP2 encodes a protein involved in the transport and presentation of antigenic peptides by MHC class I molecules and hence is a candidate locus for a putative MS susceptibility gene either through functional interactions with class I alleles or as an explanation, via linkage disequilibrium (LD), for the known association between MS and the alleles DRB1*1501, DQA1*0102, DQB1*0602. Strong LD was found between the allele TAP2*01 and DRB1*1501 in both the MS and control populations. The MS-associated haplotype can therefore be extended to DRB1*1501, DQA1*0102, DQB1*0602, TAP2*01, and the putative gene locus could reside on the centromeric side of DQ. TAP2 typing, however, could not explain the DRB1*1501, DQA1*0102, DQB1*0602-negative patients in whom, interestingly, the frequency of TAP2*01 was decreased compared to controls. The results of this study exclude TAP2 as a locus for a necessary MS/MHC gene but indicate that an MS gene carried by the DRB1*1501, DQA1*0102, DQB1*0602 haplotype could reside centromeric of DQ.

Determination of cell origin after marrow transplantation in canines by polymerase chain reaction and quantitation of the ZFY/ZFX genes.

BACKGROUND: In order to follow the course of bone marrow engraftment in dogs, and to determine the presence, and percentage, of donor-derived cells in other canine tissues, a simple and fast method of determining cell origin after sex-mismatched bone marrow transplantation was developed. METHODS: Using universal primers, fragments from genomic DNA corresponding to ZFX and ZFY genes were amplified by polymerase chain reaction. A restriction fragment length polymorphism, combined with densitometric analysis, was then used to distinguish and quantitate ZFY and ZFX sequences. Unknown samples were analyzed against standards of known mixtures of male and female DNA. RESULTS: Canine ZFY and ZFX genes were clearly resolved after amplification, digestion with HaeIII, and denaturing polyacrylamide gel electrophoresis. Microchimerism could be detected in male and female dog DNA samples derived from a range of fresh and frozen tissues including spleen, testicle, and the central nervous system. The levels of chimerism determined using this method were in either agreement with results obtained by karyotyping or more sensitive, with a detection limit of 0.4% compared with 1-2%. CONCLUSIONS: Polymerase chain reaction/restriction fragment length polymorphism detection of the ZFY and ZFX genes was found to be simple, accurate, and reliable for assessing engraftment in dogs. When compared with cytogenetic analysis, this method was found to be faster to perform, more capable of detecting lower levels of microchimerism, and useful for detecting donor-derived cells in stored specimens and in tissues other than peripheral blood or bone marrow.

Increasing the supply of cadaveric kidneys for transplantation.

The number of cadaveric kidneys currently available for transplantation is insufficient. Therefore, the Center for Disease Control (CDC) undertook a collaborative project with the two transplant programs in Georgia to increase te retrieval of cadaveric kidneys. We used retrospective analysis to select productive hospitals, hospital-specific surveillance systems to identify potential donors, and procurement and retrieval evaluation to identify preventable deficiencies. During 900 hospital months of prospective surveillance, we identified a total of 555 potential donors by death record review, giving a potential donor rate of 2.3 donors/100 deaths (110 kidneys/million population/year). We observed an increase in the number of referrals, consent obtained from next of kin, and kidneys retrieved. This period of intensive activity demonstrated that additional kidneys can be retrieved by using systematic methods.

Cost-effectiveness analysis of a rotavirus immunization program for the United States.

OBJECTIVE: To estimate the economic consequences in the United States of routine childhood immunization of children younger than 1 year of age with a rotavirus (RV) vaccine. DESIGN: Cost-effectiveness analysis of a national RV immunization program from the perspective of the health care system and the perspective of society. Estimates of disease incidence, medical expenditures, productivity costs, vaccine efficacy, and vaccine coverage rates were derived from published literature and unpublished vaccine trial reports. The impact of changes in estimates of vaccine efficacy and medical costs was determined by sensitivity analysis. MAIN OUTCOME MEASURES: Incremental cost effectiveness, expressed as savings per case of RV diarrhea prevented. RESULTS: Given a vaccine efficacy rate of 50% and a vaccine cost of $30 per dose, an RV immunization program would prevent more than 1 million cases of RV diarrhea, 58,000 hospitalizations, and 82 deaths per year. A vaccine program would cost $243 million per year but would yield net savings of $79 million from the perspective of the health care system and $466 million from the perspective of society. The incremental cost effectiveness was a savings of $459 per case prevented from the societal perspective and $78 per case prevented from the health care system perspective. Sensitivity analyses substantiated net savings over a wide range of variables, and cost effectiveness increased with greater vaccine efficacy or decreased vaccine cost. CONCLUSIONS: Economic and disease reduction benefits would be realized from the use of an RV vaccine that is partially protective against severe RV diarrhea. These findings suggest that immunization with an RV vaccine would be cost effective and cost saving.

Diabetes mellitus, impaired fasting glucose, atherosclerotic risk factors, and prevalence of coronary heart disease.

Patients with diabetes mellitus (DM), both diagnosed (history of) and undiagnosed (by fasting glucose [FG] only), as well as impaired FG have an increased risk of coronary heart disease (CHD), compared with those with normal FG. Elevations in FG levels, even in normoglycemic subjects (<110 mg/dl), may be significantly related to CHD morbidity and mortality. Improving lipid profiles and blood pressure can decrease both CHD morbidity and mortality in these patients. We evaluated the relation of glucose status to lipid levels, other risk factors, and prevalence of CHD using the 1997 American Diabetes Association diagnostic criteria in a representative sample of United States adults studied in the Third National Health and Nutrition Examination Survey from 1988 to 1994. Impaired FG, diagnosed DM, and undiagnosed DM were more prevalent in older age groups; those > or =65 years had increased prevalence compared with those <50 years old (rate ratios for IFG, DM-FG, and history of DM were 3.5, 4.8, and 10.8, respectively). Glycosylated hemoglobin levels were increased by glucose status. The frequency of known CHD risk factors also increased with worsening glucose status. Age-adjusted CHD prevalence was increased with impaired FG (rate ratio 1.47), DM-FG (rate ratio 1.56), and history of DM (rate ratio 1.72), compared with normal FG. Adjusting for age and other CHD risk factors, hyperglycemia was no longer significantly associated with CHD prevalence. Lipid values, especially high-density lipoprotein cholesterol, hypertension, and other CHD risk factors were more strongly associated with CHD than glucose status. Thus, patients with impaired FG, DM-FG, and history of DM should be considered at higher risk for CHD morbidity and mortality. However, hyperglycemia, per se, does not explain the excess risk. In addition to glucose, lipid profiles and blood pressure should be periodically monitored and appropriate treatment provided to reduce morbidity and mortality from CHD.

The DRB1 Val86/Val86 genotype associates with multiple sclerosis in Australian patients.

Genetic susceptibility to multiple sclerosis (MS) has so far been strongly localized to the MHC class II region encoding the alleles of the haplotype HLA-DRB1*1501, -DQA1*0102, -DQB1*0602. However, this haplotype is not carried by approximately 40% of MS patients; a potential explanation could be that they carry other MHC class II alleles with similar function due to the sharing of nucleotide sequences encoding critical amino acid residues. The DRB1 gene is polymorphic at residue 86, encoding valine or glycine. In view of the increasing evidence for a functional role for DRB1 aa86 in the binding and presentation of autoantigenic peptides such as myelin basic protein, this study investigated associations with the residue 86 polymorphism in an Australian MS population. A significant increase in the Val86/Val86 genotype was observed in the MS patients, which was still present in the absence of the DRB1*1501 allele (p = 0.032). This suggest that DRB1 aa86 may have an independent role in contributing to MS susceptibility. The Val86/Val86 genotype was correlated with genotyping for other putative MS susceptibility genes, including T cell receptor beta chain germline polymorphisms, HLA-DMB alleles, and -DQA1 and -DQB1 alleles encoding critical amino acid residues, with a significant interaction only observed with DQB1 Leu26 (p = 0.014). Additional studies of the HLA-DRB1 aa86 polymorphism in MS, and its function, are needed to more fully understand this association.

HLA-DMB gene and HLA-DRA promoter region polymorphisms in Australian multiple sclerosis patients.

The MHC region has been shown to contain a susceptibility locus for multiple sclerosis (MS). While the strongest association to date has been between HLA-DRB1*1501 and MS, the exact nature of the MHC association in MS remains unclear. Two candidate polymorphic loci within the MHC class II region, the HLA-DMB gene and the HLA-DRA promoter, which lie close to HLA-DRB1, were therefore examined in an Australian MS population. The HLA-DMB*0103 phenotype was increased in the MS patients (46% vs. 30%) and the frequency of the HLA-DRA promoter A allele was also increased (81% vs. 68%). When the subjects were stratified into HLA-DRB*1501 positive and negative individuals these associations were not significantly different. This is a result of the strong linkage disequilibrium between HLA-DRB*1501 and both HLA-DMB*0103 and the HLA-DRA promoter A allele. The complete linkage between DRB1*1501 and the HLA-DRA promoter A allele indicates that the MS susceptibility haplotype (DRB1*1501-HLA-DQB1*0602-HLA-DQA1* 0102) can be extended out to promoter of the HLA-DRA locus. Interactions between both HLA-DMB and the HLA-DRA promoter and other reported MS susceptibility loci were examined (TCRBV polymorphisms, HLA-DQA1 and HLA-DQB1). Some interactions between specific TCRBV polymorphisms and the HLA-DRA promoter were observed, which is consistent with other published reports suggesting an epistatic interaction between TCRBV and HLA-DRB1.

The CCR5 deletion mutation fails to protect against multiple sclerosis.

Recent advances in the understanding and identification of chemokines and their receptors have provided evidence for their consideration as candidate loci with respect to genetic susceptibility/resistance to MS. Increased levels of the chemokine, macrophage inflammatory protein (MIP)-1 alpha, have been demonstrated in the cerebrospinal fluid of both patients with MS and mice with EAE, and anti-MIP-1 alpha antibodies have been shown to prevent EAE. Recently, a common deletion mutation in the gene for the major receptor for MIP-1 alpha, chemokine receptor 5 (CCR5) has been described. Homozygotes for the mutation fail to express this receptor. Moreover, homozygotes are highly protected against HIV infection this has potential implications for the cell entry of infectious agents in other multifactorial disease where a viral component may be involved. In view of these aspects, a group of 120 unrelated Australian relapsing remitting MS and 168 unrelated control subjects were screened for the CCR5 delta 32 mutation. There was no significant difference in the allele frequency of CCR5 delta 32 gene between the MS patients (0.1125) and the control population (0.0921). The presence of two CCR5 delta 32 homozygotes in the MS patients indicates that the absence of CCR5 is not protective against MS. These data suggest that CCR5 is not an essential component in MS expression, though this may be due to redundancy in the chemokine system where different chemokine receptors may substitute for CCR5 when it is absent.

Multiple risk factors and population attributable risk for ischemic heart disease mortality in the United States, 1971-1992.

The objective of this study was to assess the associations and population attributable risks (PAR) of risk factor combinations and ischemic heart disease (IHD) mortality in the United States. We used logistic regression models to assess the association of risk factors with IHD in the First National Health and Nutrition Examination Survey (1971-1974) and Epidemiologic Follow-up Study (1982-1992) among white and black men and women. We examined eight modifiable risk factors: hypertension, elevated serum cholesterol, diabetes, overweight, current smoking, physical inactivity, depression, and nonuse of replacement hormones. Risk factors associated with IHD mortality were the same among white and black men (i.e., age, education, smoking, diabetes, hypertension, and serum cholesterol). Age, education, smoking, diabetes, and hypertension were the risk factors among white and black women. Physical inactivity, nonuse of replacement hormones, serum cholesterol, and overweight were the additional risk factors among white women. Adjusted for demographic risk factors, overall PARs for study risk factors were 41.2% for white men, 60.5% for white women (with five risk factors only), 49.2% for black men, and 71.2% for black women. Much IHD mortality attributable to individual risk factors is caused by those factors in combination with other risk factors; relatively little mortality is attributable to each risk factor in isolation. Analysis that does not examine risk factor combinations may greatly overestimate PARs associated with individual risk factors.

Is race related to glycemic control? An assessment of glycosylated hemoglobin in two South Carolina communities.

To consider the relationship between race and long-term glycemic control, as measured by glycosylated hemoglobin (GHb), we analyzed data from a community-based sample of 3175 adults in the South Carolina Cardiovascular Disease Prevention Project. A clinically meaningful difference for mean GHb levels (10.5 vs 8.4%, P < 0.001) was present between black people and white people reporting diabetes. Similarly, a significant association between race and GHb was present among people reporting "borderline diabetes" or no diabetes. Logistic regression confirmed this finding in all three diabetic categories, however, controlling for insulin use in the diabetic group reduced (P < 0.001) the association between GHb and race. These findings confirm that further improvements in glycemic control are necessary, especially for black patients and that black people not reporting diabetes have higher GHb levels compared to white people, possibly due to undiagnosed diabetes.

Sentinel health events surveillance in diabetes. Deaths among persons under age 45 with diabetes.

The pilot study for a sentinel health events surveillance system for deaths among persons under age 45 with diabetes was conducted in six states in 1984 and 1985. Two hundred and thirty-three events were identified. Information from death certificates, physicians, and families revealed that 22% died from acute complications of diabetes and 53% from chronic complications. Blood pressure measurement and urinalysis testing had been performed in the last year for almost all of the decedents, but other preventive practices were reported less frequently. Hypertension was present in 57% and of those, was not controlled in 73%. Forty-four percent were cigarette smokers at the time of death. Agreement between physicians and families was generally higher for clinical conditions than for care practices. This surveillance system appears to yield information about the health care of persons with diabetes not readily available from other sources, although modifications may be necessary before implementation.

Toxoplasma gondii isolated from amniotic fluid.

A pregnant woman contracted toxoplasmosis from exposure to oocysts shed by cats. She underwent amniocentesis for a therapeutic abortion, and Toxoplasma gondii was isolated from the amniotic fluid and placenta. This method may be useful in determining whether the fetus is infected in cases of toxoplasmosis acquired during pregnancy.

Babesiosis in post-splenectomy hosts.

Two persons who had been splenectomized later contracted babesiosis, one on Cape Cod and one near Islip, Long Island, areas where human cases of babesiosis had not been previously identified. One of the patients received pentamidine, but parasitemia persisted after therapy. No deaths have been recorded for persons who had had splenectomies and were later infected with Babesia microti. Until more effective therapy is available, such patients should be treated conservatively.

The effectiveness of insecticide-impregnated bed nets in reducing cases of malaria infection: a meta-analysis of published results.

The use of insecticide-impregnated bed nets to minimize human-vector contact may reduce the incidence of malaria. Consequently, several field trials have evaluated their effectiveness as a malaria prevention strategy. A meta-analysis of published reports of field trials that measured the incidence of infections was performed to provide a measure of the effectiveness of insecticide-treated bed nets in preventing clinical malaria. Subsetted analyses were performed on the 10 field trials to calculate pooled incidence rate ratios of infection among the study groups. For the studies comparing insecticide-impregnated bed nets with untreated bed nets, the summary incidence rate ratio for acquiring malarial infections was 0.757 (95% confidence interval [CI] = 0.612-0.938), representing a reduction of 24%. For the studies comparing permethrin-impregnated bed nets with controls without bed nets, the summary incidence rate ratio was 0.497 (95% CI = 0.417-0.592) (Rothman-Boice heterogeneity statistics = 17.27 [P = 0.004] and 23.55 [P = 0.0003], respectively). These data suggest that insecticide-impregnated bed nets are effective in preventing malaria, decreasing the incidence rate ratio by approximately 50% in field trials performed to date.

An ounce of prevention ... what are the returns? Second edition, 1999.

CONTEXT: Because human and financial resources are limited, health efforts must focus on prevention strategies that yield the most benefit for the investment. Many current strategies identified in the literature offer opportunities to promote health at a reasonable cost. OBJECTIVE: To present a literature-based review of evidence demonstrating that prevention can be an effective and wise use of resources through CDC's An Ounce of Prevention ... What Are the Returns? Second Edition. DESIGN: Systematic review of cost-effectiveness literature for a selected group of prevention strategies. SETTING: Prevention strategies relevant to the U.S. population. RESULTS: Data indicate that the health conditions considered can be addressed through prevention strategies that are either cost effective or cost saving. CONCLUSIONS: An Ounce of Prevention ... What Are the Returns? Second Edition can be used to conveniently access information on prevention strategies, the diseases and injuries they address, and their cost effectiveness. It also complements other comprehensive prevention guides. However, limitations of the available cost-effectiveness studies indicate that standardized procedures should be followed for studies of all recommended prevention strategies. Researchers must standardize review procedures to improve both the quality and comparability of studies.