Statistical and methodological challenges for disaster preparedness and medical needs assessment in Rio Grande Valley of Texas

In recent years, disaster preparedness through assessment of medical and special needs persons (MSNP) has taken a center place in public eye in effect of frequent natural disasters such as hurricanes, storm surge or tsunami due to climate change and increased human activity on our planet. Statistical methods complex survey design and analysis have equally gained significance as a consequence. However, there exist many challenges still, to infer such assessments over the target population for policy level advocacy and implementation. ^ Objective. This study discusses the use of some of the statistical methods for disaster preparedness and medical needs assessment to facilitate local and state governments for its policy level decision making and logistic support to avoid any loss of life and property in future calamities. ^ Methods. In order to obtain precise and unbiased estimates for Medical Special Needs Persons (MSNP) and disaster preparedness for evacuation in Rio Grande Valley (RGV) of Texas, a stratified and cluster-randomized multi-stage sampling design was implemented. US School of Public Health, Brownsville surveyed 3088 households in three counties namely Cameron, Hidalgo, and Willacy. Multiple statistical methods were implemented and estimates were obtained taking into count probability of selection and clustering effects. Statistical methods for data analysis discussed were Multivariate Linear Regression (MLR), Survey Linear Regression (Svy-Reg), Generalized Estimation Equation (GEE) and Multilevel Mixed Models (MLM) all with and without sampling weights. ^ Results. Estimated population for RGV was 1,146,796. There were 51.5% female, 90% Hispanic, 73% married, 56% unemployed and 37% with their personal transport. 40% people attained education up to elementary school, another 42% reaching high school and only 18% went to college. Median household income is less than $15,000/year. MSNP estimated to be 44,196 (3.98%) [95% CI: 39,029; 51,123]. All statistical models are in concordance with MSNP estimates ranging from 44,000 to 48,000. MSNP estimates for statistical methods are: MLR (47,707; 95% CI: 42,462; 52,999), MLR with weights (45,882; 95% CI: 39,792; 51,972), Bootstrap Regression (47,730; 95% CI: 41,629; 53,785), GEE (47,649; 95% CI: 41,629; 53,670), GEE with weights (45,076; 95% CI: 39,029; 51,123), Svy-Reg (44,196; 95% CI: 40,004; 48,390) and MLM (46,513; 95% CI: 39,869; 53,157). ^ Conclusion. RGV is a flood zone, most susceptible to hurricanes and other natural disasters. People in the region are mostly Hispanic, under-educated with least income levels in the U.S. In case of any disaster people in large are incapacitated with only 37% have their personal transport to take care of MSNP. Local and state government’s intervention in terms of planning, preparation and support for evacuation is necessary in any such disaster to avoid loss of precious human life. ^ Key words: Complex Surveys, statistical methods, multilevel models, cluster randomized, sampling weights, raking, survey regression, generalized estimation equations (GEE), random effects, Intracluster correlation coefficient (ICC).^

Therapeutic potential of p53 restoration in spontaneous tumors

Over 80% of p53 mutations found in human cancers are p53 missense mutations. Recent studies have shown that p53 restoration leads to tumor regression in mice with p53 deletions, but the therapeutic efficacy of p53 restoration in tumors containing p53 missense mutations has not been evaluated. Since p53 mutant such as p53R172H has gain-of-function activities and dominant-negative effect that repress wild type p53, the activity of restored wild-type p53 might be compromised by the mutant p53 in tumors. We hypothesized that p53 restoration in tumors with the p53R172H mutation may be less therapeutically effective as p53 restoration in tumors null for p53. I tested this hypothesis by comparison of the therapeutic outcomes of p53 restoration in mice with spontaneous tumors that either lacked p53 or contained the p53R172H mutation. While p53 restoration causes tumor regression in mice lacking p53, the same p53 restoration halts tumor progression in mice with the p53R172H mutation. This phenotypic difference suggests a dominant-negative activity of the mutant p53. Moreover, I showed that the mutant p53 only inhibits part of the activity of the restored wild-type p53 and that the remaining wild-type activity still causes a delay in tumor progression. We conclude that p53 restoration has therapeutic potential in p53R172H tumors via suppression of tumor progression. This knowledge is of critical importance for p53 targeted cancer therapy because many patients with cancers harbor p53 missense mutations rather p53-null mutations. Since p53R172H mutation represents one of the most frequent and potent p53 missense mutations observed in human cancers, the current findings implicates that p53 restoration may be therapeutically important not only in human cancers characterized by loss of p53 alleles but also in those in which p53 missense mutations play an important pathogenetic role. ^

A literature review of the use of DDT to fight malaria

Background. First synthesized in 1874, dichlorodiphenyltrichloroethane (DDT) was not used until the second half of World War II after its insecticidal properties were discovered in 1939. For decades DDT has been used globally with the intent of eradicating malaria. This began in 1955 when the eighth World Health Assembly launched a global campaign selecting DDT as the chemical of choice for the eradication of malaria. The United States banned DDT use in 1972 partially due to the publication of “Silent Spring” by Rachel Carson in 1962 which suggested that DDT was harmful to the environment, wildlife and is a carcinogen. ^ Objectives. To critically review the literature on DDT, and evaluate its importance in malaria prevention and control. Methods: The design of this systematic literature review is a narrative summary and evaluation of the papers reviewed. The data came from searches using PubMed and MEDLINE which are free and publicly available databases. Inclusive criteria that were considered during the search are English language peer reviewed journal articles published in the last 20 years. The keywords were: “insecticidal and agricultural use of DDT”, “human impact of malaria”, “economic impact of malaria”, “benefits of DDT”, “effects of DDT”, “importance of malaria control”, and alternatives to DDT for malaria control. ^ Results. Malaria continues to be one of the most common infectious diseases and creates a tremendous global public health problem. WHO recommends DDT for malaria vector control because compared to other pesticides, it is the most persistent in indoor spraying. ^ Conclusion. Indoor spraying of DDT in malaria endemic areas may cause increased exposure of the chemical to humans; however I conclude that the overall benefits outweigh the risks because more lives are saved due to fewer infections with malaria.^

Concordance between medical records and personal interview in ascertaining breast cancer and diabetes status: Analysis of the south Texas women's health project

Accurate ascertainment of risk factors and disease status is vital in public health research for proper classification of research subjects. The two most common ways of obtaining this data is by self-report and review of medical records (MRs). South Texas Women’s Health Project was a case-control study looking at interrelationships between hormones, diet, and body size and breast cancer among Hispanic women 30-79 years of age. History of breast cancer, diabetes mellitus (DM) and use of DM medications was ascertained from a personal interview. At the time of interview, the subject identified her major health care providers and signed the medical records release form, which was sent to the designated providers. The MRs were reviewed to confirm information obtained from the interview.^ Aim of this study was to determine the sensitivity and specificity between MRs and personal interview in diagnosis of breast cancer, DM and DM treatment. We also wanted to assess how successful our low-cost approach was in obtaining pertinent MRs and what factors influenced the quality of MR or interview data. Study sample was 721 women with both self-report and MR data available by June 2007. Overall response rate for MR requests was 74.5%. MRs were 80.9% sensitive and 100% specific in confirming breast cancer status. Prevalence of DM was 22.7% from the interviews and 16% from MRs. MRs did not provide definite information about DM status of 53.6% subjects. Sensitivity and specificity of MRs for DM status was 88.9% and 90.4% respectively. Disagreement on DM status from the two sources was seen in 15.9% subjects. This discordance was more common among older subjects, those who were married and were predominantly Spanish speaking. Income and level of education did not have a statistically significantly association with this disagreement.^ Both self-report and MRs underestimate the prevalence of DM. Relying solely on MRs leads to greater misclassification than relying on self-report data. MRs have good to excellent specificity and thus serve as a good tool to confirm information obtained from self-report. Self-report and MRs should be used in a complementary manner for accurate assessment of DM and breast cancer status.^

A study of the relationship of support systems and adolescent pregnancy outcomes in an adolescent family life project

This study analyzed the relationship of family support systems and adolescent pregnancy outcomes. The population for the study was 390 adolescents who had attended the Marion County Health Department Adolescent Family Life Project in Indianapolis, Indiana during a two-year period.^ The study is unique in that it afforded the opportunity to compare adolescent pregnancy-related characteristics, of white and non-white adolescents in the same study.^ The pregnancy outcomes studied were: Infant birthweight, school attendance, and pregnancy recidivism.^ Significant results were found in the analysis that supported other research in regard to factors that are associated with school attendance when family support, adolescent's age, and ethnicity were controlled. Infant birthweight and repeat pregnancy outcome relationships were not found to have any consistently significant relationship with independent variables anticipated to be associated. However, the comparisons of infant birthweight among the adolescents with, and without, family support, by ethnicity resulted in some interesting findings. Repeat pregnancy proved an enigma, in that there seemed to be almost no variables in this study that were associated with the adolescent having a repeat pregnancy.^ Familial support in this study seemed to be of less importance as a factor in adolescent pregnancy outcomes than was ethnicity. The non-white adolescents in this study had a better record for remaining in school, both those non-white adolescents who lived with parents, and those who did not live with parents. More low birthweight occurred in the non-white adolescent, both those adolescents who lived with parents, and those who did not live with parents. Repeat pregnancy occurred more in the non-white adolescent whether she lived with parents, or did not live with parents. ^

A study to determine the association between medical decision-making and the performance of an institutional ethics committee

This study developed proxy measures to test the independent effects of medical specialty, institutional ethics committee (IEC) and the interaction between the two, upon a proxy for the dependent variable of the medical decision to withhold/withdraw care for the dying--the resuscitation index (R-index). Five clinical vignettes were constructed and validated to convey the realism and contextual factors implicit in the decision to withhold/withdraw care. A scale was developed to determine the range of contact by an IEC in terms of physician knowledge and use of IEC policy.^ This study was composed of a sample of 215 physicians in a teaching hospital in the Southwest where proxy measures were tested for two competing influences, medical specialty and IEC, which alternately oppose and support the decision to withhold/withdraw care for the dying. A sub-sample of surgeons supported the hypothesis that an IEC is influential in opposing the medical training imperative to prolong life.^ Those surgeons with a low IEC score were 326 percent more likely to continue care than were surgeons with a high IEC score when compared to all other specialties. IEC alone was also found to significantly predict the decision to withhold/withdraw care. Interaction of IEC with the specialty of surgery was found to be the best predictor for a decision to withhold/withdraw care for the dying. ^

MEDICAL CARE UTILIZATION IN TIME AMONG ELDERLY MEDICARE ENROLLEES IN AN HMO

Investigation into the medical care utilization of elderly Medicare enrollees in an HMO (Kaiser - Portland, Oregon): The specific research topics are: (1) The utilization of medical care by selected determinants such as: place of service, type of service, type of appointment, physician status, physician specialty and number of associated morbidities. (2) The attended prevalence of 3 chronic diseases: hypertension, diabetes and arthritis in addition to pneumonias as an example of acute diseases. The selection of these examples was based on their importance in morbidity/or mortality results among the elderly. The share of these diseases in outpatient and inpatient contacts was examined as an example of the relation between morbidity and medical care utilization. (3) The tendency of individual utilization patterns to persist in subsequent time periods. The concept of contagion or proneness was studied in a period of 2 years. Fitting the negative binomial and the Poisson distributions was applied to the utilization in the 2nd year conditional on that in the 1st year as regards outpatient and inpatient contacts.^ The present research is based on a longitudinal study of 20% random sample of elderly Medicare enrollees. The sample size is 1683 individuals during the period from August 1980-December 1982.^ The results of the research were: (1) The distribution of contacts by selected determinants did not reveal a consistent pattern between sexes and age groups. (2) The attended prevalence of hypertension and arthritis showed excess prevalence among females. For diabetes and pneumonias no female excess was noticed. Consistent increased prevalence with increasing age was not detected.^ There were important findings pertaining to the relatively big share of the combined 3 chronic diseases in utilization. They accounted for 20% of male outpatient contacts vs. 25% of female outpatients. For inpatient contacts, they consumed 20% in case of males vs. 24% in case of females. (3) Finding that the negative binomial distribution fit the utilization experience supported the research hypothesis concerning the concept of contagion in utilization. This important finding can be helpful in estimating liability functions needed for forecasting future utilization according to previous experience. Such information has its relevance to organization, administration and planning for medical care in general. (Abstract shortened with permission of author.) ^

Academic medical centers: A framework for strategic repositioning

This study sought to understand the elements affecting the success or failure of strategic repositioning efforts by academic medical centers (AMC). The research question was: What specific elements in the process appear to be most important in determining the success or failure of an AMC.s strategic repositioning? Where success is based on the longterm sustainability of the new position.^ "An organization's strategic position is its perceptual location relative to others" (Gershon, 2003). Hence, strategic repositioning represents a shift from one strategic position within an environment to another (H. Mintzberg, 1987a). A deteriorating value proposition coupled with an unsustainable national health care financing system is forcing AMCs to change their strategic position. Where the value proposition is defined as the health outcome per dollar spent. ^ AMCs are of foundational importance to our health care system. They educate our new physicians, generate significant scientific breakthroughs, and care for our most difficult patients. Yet, their strategic, financial and business acumen leaves them particularly vulnerable in a changing environment. ^ After a literature review revealed limited writing on this subject, the research question was addressed using three separate but parallel exploratory case study inquiries of AMCs that recently underwent a strategic repositioning. Participating in the case studies were the Baylor College of Medicine, the University of Texas M. D. Anderson Cancer Center, and the University of Texas Medical Branch.^ Each case study consisted of two major research segments; a thorough documentation review followed by semi-structured interviews of selected members of their governance board, executive and faculty leadership teams. While each case study.s circumstances varied, their response to the research question, as extracted through thematic coding and analysis of the interviews, had a high degree of commonality.^ The results identified managing the strategic risk surrounding the repositioning and leadership accountability as the two foundational elements of success or failure. Metrics and communication were important process elements. They both play a major role in managing the strategic repositioning risk communication loop. Sustainability, the final element, was the outcome sought.^ Factors leading to strategic repositioning included both internal and external pressures and were primarily financial or mission based. Timing was an important consideration as was the selection of the strategic repositioning endpoint.^ In conclusion, a framework for the strategic repositioning of AMCs was offered that integrates the findings of this study; the elements of success, the factors leading to strategic repositioning, and the risk communication loop. ^

THE NEW ROLE OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9: A CONNECTION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9, APOLIPOPROTEIN B, and AUTOPHAGY

Plasma low-density lipoprotein (LDL) levels are positively correlated with the incidence of coronary artery disease. In the circulation, the plasma LDL clearance is mainly achieved by the uptake via LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a newly discovered gene, playing an important role in LDL metabolism. Gain-of-function mutations of PCSK9 lead to hypercholesterolemia and loss-of-function mutations of PCSK9 are associated with decrease of LDL cholesterol. The effects of PCSK9 on cholesterol levels are the consequence of a strong interaction between the catalytic domain of PCSK9 and epidermal growth factor-like repeat A (EGF-A) domain of LDLR on the cell surface of hepatocytes. This PCSK9/LDLR complex enters the cell via endocytosis, where both PCSK9 and LDLR are removed via the lysosome pathway, resulting in decreased levels of LDLR and accumulation of LDL in the plasma. However, whether this is the exclusive function of PCSK9 on LDL metabolism was challenged by us; we observed PCSK9 interacted with apolipoprotein B (apoB) and increased apoB production, irrespective of the LDLR. ApoB is the primary structure protein of LDL particle and it also serves as the ligand for the LDL receptor. There is ample evidence showing that the levels of apoB are a better indicator for heart disease than either total cholesterol or LDL cholesterol levels. We used a second-generation adenoviral vector to overexpress PCSK9 (Ad-PCSK9) in wild-type C57BL/6 and LDLR deficient mice (Ldlr-/- and Ldlr-/-Apobec1-/-). Our study revealed that overexpression of PCSK9 promoted the production and secretion of apoB in the form of very-low density lipoprotein (VLDL), which is the precursor of LDL, in the 3 mouse models studied (C57BL/6J, Ldlr-/-, and Ldlr-/-Apobec1-/-). The increased apoB production in mice was regulated at post-transcriptional levels, since there was no difference in apoB mRNA levels between mice treated with Ad-PCSK9 and control vector Ad-Null. By using pulse-chase experiment on primary hepatocytes, we showed that overexpression of PCSK9 increased the secretion of apoB, independent of LDLR. In the circulation, we showed that PCSK9 was associated with LDL particles. By using 3 different protein–protein interaction assays of co-immunoprecipitation, mammalian two-hybrid system, and in situ proximity ligation assay, we demonstrated a direct protein–protein interaction between PCSK9 and apoB. The impact of this interaction inhibited the physiological removal process of apoB via autophagosome/lysosome pathway in an LDLR-independent fashion, resulting in increased production and secretion of apoB-containing lipoproteins. The significance of this process was shown in the Pcsk9 knockout mice in the background of Ldlr-/-Apobec1-/- mice (triple knockout mice); in the absence of Pcsk9 (triple knockout mice) the levels of cholesterol, triacylglycerol, and apoB decreased significantly in comparison to that of Ldlr-/-Apobec1-/- mice. Taken together, our study demonstrated a direct intracellular interaction of PCSK9 with apoB, resulting in the inhibition of apoB degradation via the autophagosome/lysosome pathway independent of LDLR. This discovery provides a new concept of the importance of PCSK9 and suggests new approaches for the therapeutic intervention of hyperlipidemia.

1906 Polk's Medical Register and Directory of North America (Texas Portion Only)

List of Physicians and Surgeons arranged by location, giving post office address with population and location, the School practiced, date and college of graduation, all the existing and extinct medical colleges in North America, with locations, officers, number of professors, lecturers, demonstrators, etc., the various medical societies, penal, reformatory and charitable state institutions, hospitals, sanitariums, dispensaries, asylums and other medical institutions, boards of health, boards of medical examiners, health officers at principal points, the laws of registration and other laws relating to the profession, medical journals with names of editors, frequency of publication and subscription rates, medical libraries, a therapeutic classification of American health resorts, mineral springs, official list of officers of the medical departments of the U.S. Army, Navy and Marine Hospital Service, the U.S. Indian Service, roster of examining surgeons of the U.S. Pension Department, a descriptive sketch of each state, territory and province, embodying such matters as location, boundary, extent in miles and acres, latitude and longitude, statistics relating to climate, temperature, rate of mortality, etc. Full particulars of all national and inter-state associations and societies relating to medicine and surgery, and an INDEX TO THE PHYSICIANS OF THE UNITED STATES. Arranged alphabetically, with the number of the page and column in which the name appears.

1902 Polk's Medical Register and Directory of the United States and Canada (Texas portion only)

List of Physicians and Surgeons arranged by states and provinces, giving post office address with population and location, the School practiced, date and college of graduation, all the existing and extinct medical colleges in the United States and Canada, with locations, officers, number of professors, lecturers, demonstrators, etc., the various medical societies, state prisons, hospitals, sanitariums, dispensaries, asylums and other medical institutions, boards of health, boards of medical examiners, a synopsis of the laws of registration and other laws relating to the profession, medical journals with names of editors, frequency of publication and subscription rates, medical libraries, mineral springs, official list of officers of the medical departments of the U.S. Army, Navy and Marine Hospital Service, roster of examining surgeons of the U.S. Pension Department, a descriptive sketch of each state, territory and province, embodying such matters as location, boundary, extent in miles and acres, latitude and longitude, statistics relating to climate, temperature, rate of mortality, number of deaths from consumption, etc. full particulars of all national associations and societies relating to medicine and surgery, and an INDEX TO THE PHYSICIANS OF THE UNITED STATES. Arranged alphabetically, with the number of the page on which the name appears.

The impact of communication and cultural diversity in utilizing dental services among Saudi Arabian students in U.S.A.

Objectives: The purpose of this study is to understand the perceived effects of patient-dental staff communication and cultural diversity on the utilization of dental services in the U.S. by Saudi Arabian students who live in the U.S. and enrolled into the King Abdullah Scholarship program. Methods: The study design was an analytical cross-sectional study. Data for this study was obtained from the Saudi Dental Servicers Utilization Survey, a voluntary internet survey available online for one month through Facebook. Ordered logistic regression analyses and multinomial logistic regression analyses were used to measure the relationships between patient-dental staff communication and cultural diversity on the utilization of dental services. Results: Eight hundred and forty-seven responses were analyzed for this study. Overall, the majority of Saudi students reported having excellent communication experience with dental providers in the U.S. More than 58% of respondents reported at least one regular dental visit last year. Factors that influenced the use of regular dental care were: dentist's explanation of treatment plan, response of dental staff to patient's needs, respectful and polite dental staff, dental staff kindness, availability of up-to-date equipment, and overall communication with dentist. However, the utilization of emergency dental care was not associated with any measurement of patient-dental provider communication. Overall future utilization of dental care is associated with all aspects of patient-dental staff communication measured in this survey. Furthermore, more utilization of regular dental care was related to respondent's perception of the importance of trustworthiness dental staff and the importance of a dentist's reputation was only marginally associated. Respondent's perception of dentist's reputation was associated with more use of emergency dental services. Respondents are more likely to anticipate using dental care in the future if they perceived trustworthiness dental staff, and the dentist's reputation as influencing factors to their usage of dental services. Conclusions: Patient-dental staff communication was partially associated with utilization of regular dental care, not associated with utilization of emergency dental care, and broadly associated with anticipated future utilization of dental care. In addition, trustworthy dental staff, and a dentist's reputation were considered to be strong influencing factors towards utilization of dental services.^

The effects of IL -10 producing monocytes on T-cell activation in patients with epithelial ovarian cancer

A newly described subset of monocytes has been identified in peritoneal exudate cells (PEC) from the malignant ascites of patients with ovarian cancer. These cells were characterized by the production of IL-10 and TGF-β2, but not IL-12, IL-1α, or TNF-α, and expressed CD14, CD16, and CD54, but not HLA-DR, CD80, CD86, CD11a, CD11b, or CD25 cell surface antigens. Since this subset of monocytes could affect the modulation of tumor immune responses in vivo, studies were undertaken to determine their effect on the activation and proliferation of autologous T-cells from the peritoneal cavity of patients with ovarian carcinoma. Cytokine transcripts, including IL-2, GM-CSF, and IFN-γ were detected in T-cells isolated from patient specimens that also contained the IL-10 producing monocytes, although the IFN-γ and IL-2 proteins could not be detected in T-cells co-incubated with the IL-10 producing monocytes in vitro. Additionally, IL-10 producing monocytes co-cultured with autologous T-cells inhibited the proliferation of the T-cells in response to PHA. T-cell proliferation and cytokine protein production could be restored by the addition of neutralizing antibodies to IL-10R and TGF-β to the co-culture system. These results suggested that this subset of monocytes may modulate antitumor immune responses by inhibiting T-cell proliferation and cytokine protein production. Further studies determined that the precursors to the inhibitory monocytes were tumor-associated and only present in the peripheral blood of patients with ovarian cancer and not present in the peripheral blood of healthy donors. These precursors could be induced to the suppressor phenotype by the addition of IL-2 and GM-CSF, two cytokines detected in the peritoneal cavity of ovarian cancer patients. Lastly, it was shown that the suppressor monocytes from the peritoneal cavity of ovarian cancer patients could be differentiated to a non-inhibitory phenotype by the addition of TNF-α and IFN-γ to the culture system. The differentiated monocytes did not produce IL-10, expressed the activation antigens HLA-DR, CD80, and CD86, and were able to stimulate autologous T-cells in vitro. Since a concomitant reduction in immune function is associated with tumor growth and progression, the effects of these monocytes are of considerable importance in the context of tumor immunotherapy. ^

Characterization of anti -sulfatide autoantibodies in demyelinating diseases

Multiple sclerosis (MS) is the most common autoimmune disease of the central nerve system and Guillain Barré Syndrome (GBS) is an inflammatory neuropathy involving the peripheral nerves. Anti-myelin immunoglobins may play a role in the demyelination processes of the both diseases. Sulfatide is an abundant glycolipid on myelin and is a candidate target antigen for disease related autoantibodies. The objective of this study was to characterize anti-sulfatide antibodies and compare antibodies from GBS and MS patients with fetal antibodies. Our hypothesis is that some B cells producing disease-associated autoantibodies are derived from or related to B cells of the fetal repertoire. Here we report that reactivity of plasma IgM against sulfatide was elevated in twelve MS patients compared with twelve normal subjects. This result implies that anti-sulfatide antibodies are disease-related. A total of sixteen human B lymphocyte clones producing anti-sulfatide autoantibodies were isolated from MS patients, GBS patients and a human fetus. Seven of the clones were from three MS patients, four of the clones were from three GBS patients and five were from the spleen of a twenty-week human fetus. Sequences have been obtained for the heavy and light chain variable regions (VDJ and VJ regions) of all of the anti-sulfatide immunoglobulins. Seven of the sixteen antibodies used VH3 for the variable region gene of the heavy chain consistent with the rate of VH3 usage in randomly selected B cells. Somatic mutations were significantly more frequent in the patient antibodies than in the fetus and somatic mutations in CDR's (Complementarity Determining Region) were significantly more frequent than in framework regions. No significant difference was found between patients and fetus in length of VH CDRIII. However, it is reported that antibodies from randomly selected normal adult B cells have longer CDRIII lengths than those of the fetus (Sanz I, 1991 Journal of Immunology Sep 1;147(5):1720-9). Our results are consistent with derivation of the precursors of B cells producing these autoantibodies from B cells related to those of the fetal repertoire. These findings are consistent with a model in which quiescent B cells from clones produced early in development undergo proliferation in dysregulated disease states, accumulating somatic mutations and increasing in reactivity toward self-antigens. ^ Epitope mapping and molecular modeling were done to elucidate the relationships between antibody structure and binding characteristics. The autoantibodies were tested for binding activity to three different antigens: sulfatide, galactoceramide and ceramide. Molecular modeling suggests that antibodies with positive charge surrounded by or adjacent to hydrophobic groups in the binding pocket bind to the head of sulfatide via the sulfate group through electrostatic interactions. However, the antibodies with hydrophobic groups separated from positive charges appear to bind to the hydrophobic tail of sulfatide. This observation was supported by a study of the effect of NaCl concentration on antigen binding. The result suggested that electrostatic interactions played a major role in sulfate group binding and that hydrophobic interactions were of greater importance for binding to the ceramide group. Our three-dimensional structure data indicated that epitope specificity of these antibodies is more predictable at the level of tertiary than primary structure and suggested positive selection based on structure occurred in the. formation of those autoantibodies. ^